Choriogonadotropin alfa for injection - Ovidrel; human chorionic gonadotropin, recombinant
Status - approved; marketed
Organizations involved:
EMD Serono, Inc. – Manuf.; R&D; Tech.; USA mark.
Merck Serono S.A. – Intl. mark.; Parent
Merck KGaA – Parent
Serono Labs. Inc. – Former
Serono International S.A. – Former
Serono, Inc. – Former
Description: Choriogonadotropin alfa for injection or Ovidrel refers to lyophilized (freeze-dried) and aqueous (prefilled syringe) formulations of recombinant choriogonadotropin alfa (recombinant human chorionic gonadotropin; r-hCG; rhCG) glycoprotein produced by a transformed Chinese hamster ovary (CHO) cell line. Choriogonadotropin alfa is a water soluble glycoprotein human sex hormone consisting of two non-covalently linked subunits - alpha (a) and beta (b) chains - consisting of 92 and 145 amino acid residues, respectively, with carbohydrate moieties linked to Asn-52 and Asn-78 on the alpha subunit and on Asn-13, Asn-30, Ser-121, Ser-127, Ser-132 and Ser-138 of the beta subunit. The alpha-hCG subunit, common to all the gonadotropin hormones (FSH, TSH, LH, hCG), is 92 amino acid residues in length and the beta-hCG subunit, which dictates the hormone specificity, is 145 amino acid residues in length. Choriogonadotropin has a molecular weight of 2,5719.7 Dalton (25.8 kDa).
The primary structure of the alpha chain of rhCG is identical to that of the alpha chain of native human hCG, follicle stimulating hormone (FSH) and luteinizing hormone (LH). The glycoform (glycosylation pattern) of the alpha subunit of rhCG is closely comparable to that of hCG derived from the urine of pregnant women (u-hCG), with the differences mainly being due to the branching and extent of sialylation of the oligosaccharides. The beta chain has both O- and N-glycosylation sites, and its structure and glycosylation pattern are also very similar to that of u-hCG. rhCG has been shown clinically equivalent to human u-hCG, which has long been used in standard treatment regimens.
hCG products are used for treatment of both female and male infertility. In the female, the action of hCG, either derived from human urine or recombinant, is luteinization, promoting corpus luteum formation and progesterone secretion. Ovidrel is, to date, only approved for treatment of anovulation, the most common cause of female infertility. In this context, Ovidrel (or another hCG product) is administered after ovarian stimulation with follicle stimulating hormone (FSH, e.g., Gonal-f) to trigger ovulation to promote the final maturation of eggs in the ovaries of women undergoing assisted reproductive technologies (ART), such as in-vitro fertilization (IVF). hCG is only given in cases where the cause of infertility has been clinically documented.
In the male, hCG promotes testosterone secretion and, in association with follicle stimulating hormone (FSH), it initiates and maintains spermatogenesis. hCG also induces testicular descent in boys with cryptorchidism (undescended testicles) when no anatomical obstruction exists.
Ovidrel is the only hCG product in the U.S. approved for subcutaneous injection (with a small needle under the skin), making (self)administration more convenient. Other hCG products, all u-hCG, are injected intramuscularly, which can often be painful and usually requires the assistance of a partner or healthcare provider. Ovidrel has a higher level of purity than u-hCG products, permitting the use of more accurate and precise assays to measure product strength than is possible with non-homogenous urine-derived products.
The biological activity of choriogonadotropin alfa is determined using the seminal vesicle weight gain test in male rats described in the “Chorionic Gonadotrophins” monograph of the European Pharmacopoeia, with in vivo activity calibrated against the third international reference preparation, IS75/587, for chorionic gonadotropin.
Ovidrel lyophilized powder is packaged in vials for subcutaneous (SC) injection after reconstitution with Sterile Water for Injection, USP. Each vial contains 285 µg of choriogonadotropin alfa, 30 mg sucrose, 0.98 mg phosphoric acid, and sodium hydroxide (for pH adjustment). After reconstitution, this delivers 250 µg of recombinant choriogonadotropin alfa. The pH of reconstituted solution is 6.5 to 7.5. Nitrogen is used as an inert gas to fill the head space of the vial.
Ovidrelle Prefilled Syringe for subcutaneous injection is filled with 0.515 mL containing 257.5 µg of choriogonadotropin alfa (for delivery of 250 µg), 28.1. mg mannitol, 505 µg 85% O-phophoric acid, 103 µg L-methionine, 51.5 µg poloxamer 188, sodium hydroxide (pH adjustment), and Water for Injection for delivery of 250 µg of choriogonadotropin alfa/0.5 mL.
Most current and prior hCG products contain hCG extracted from the urine of pregnant women. This involves the collection an processing of large amounts of urine from post-menopausal women..
Nomenclature: hCG, rDNA [BIO]; Ovidrel [TR]; Choriogonadotropin [FDA]; Ovitrelle [TR in Europe]; human chorionic gonadotropin, recombinant [SY]; rhCG [SY]
Companies.: Ovidrel was developed and is manufactured and marketed internationally by Serono International S.A. In Jan. 2007, Merck KGaA acquired Serono, and the company was renamed Merck Serono S.A. Serono Labs. Inc., now EMD Serono, Inc., markets the product in the U.S.
The solution for injection in a pre-filled syringe is manufactured and released at Industria Farmaceutica Serono S.p.A, Bari, Italy. Packaging may also take place at Laboratoires Serono S.A., Aubonne, Coinsins, Switzerland.
Manufacture: Production involves expansion of genetically modified Chinese Hamster Ovary (CHO) cells from an extensively characterized cell bank into large scale cell cultures. Choriogonadotropin alfa is secreted by the CHO cells directly into the cell culture medium and purified using a series of chromatographic steps. The purification procedure for r-hCG involves a series of ultrafiltration units, chromatographic columns and viral nanofiltration This yields a product with a high level of purity and consistent product characteristics, including glycoforms and biological activity. The standard batch size can range from 16,000 to 52,500 vials.
Choriogonadotropin alfa is manufactured using a serum free cell culture process. However, a small amount of fetal bovine serum (FBS) is used in the inoculation phase of the manufacturing process. FBS was derived from animals sourced in the U.S. and Canada, which are BSE-free countries. The manufacturing process also involves the use of trypsin of porcine origin. It is certified to be porcine parvovirus free, to comply with 9 CFR 113.53, and that
its production involves an extended extraction at acid pH. According to EMEA/EU, "The viral safety with regard to trypsin is therefore considered to be sufficiently ensured."
FDA class: Drug NDA
Approvals: Date = 20000927; NDA 21-149
Date = 20031008; NDA supplement; Indication = approval of prefilled syringe
Date = 20070730; NDA supplement; Indication = addition of a Postmarketing Reports subsection to the ADVERSE EVENTS section, changes to the HOW SUPPLIED section, and other editorial changes to the insert/labeling
Indications: [full text of the "INDICATIONS AND USAGE” section of the product insert/labeling]:
Ovidrel (choriogonadotropin alfa for injection) is indicated for the induction of final follicular maturation and early luteinization in infertile women who have undergone pituitary desensitization and who have been appropriately pretreated with follicle stimulating hormones as part of an Assisted Reproductive Technology (ART) program such as in vitro fertilization and embryo transfer. Ovidrel is also indicated for the induction of ovulation (OI) and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.
Selection of Patients: 1. Before treatment with gonadotropins is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Ovidrel only if enrolled in an in vitro fertilization program. 2. Primary ovarian failure should be excluded by the determination of gonadotropin levels. 3. Appropriate evaluation should be performed to exclude pregnancy. 4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting FSH and Ovidrel therapy. 5. Evaluation of the partner’s fertility potential should be included in the initial evaluation.
Status: Choriogonadotropin alfa was the first new recombinant molecule to receive approval for the treatment of infertility since the approval of recombinant follicle stimulating hormone.
On Oct. 19, 200,l Ovidrel/Ovitrelle was approved and in the European Union (EU). On Oct. 30, 2003, EU approval was granted to the prefilled syringe formulation of Ovitrelle.
In July 2011, Ovitrelle received European Union supplemental approval for packaging in prefilled pen injectors designed to increase compliance during fertility treatment. After administration the pens immediately confirm if a complete dose was delivered. If an incomplete dose was delivered the pen informs the user of the missing amount.
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Tech. transfer:
U.S. 4,840,896 was extended by 1,044 days, and expired on April 29, 2009.
As claimed in the Orange Book, U.S. 5767251, Recombinant heterodimeric human fertility hormones, and methods, cells, and vectors and DNA for the production thereof, assigned to Genzyme, expiring June 16, 2015. The Orange Book also cites 6,706,681, "HCG liquid formulations," expiring March 21, 2017.
EP 0211894, "FSH," and EP 0521586, Recombinant FSH," both expired in 2006.
EP 0487512 and EP 0160699, "Production of heterodimeric human fertility hormones," both expired in 2004.
EP 0814841, "HCG LIQUID FORMULATIONS," expired in 2005.
Serono was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Serono and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Disease: Approximately one in ten couples of reproductive age experiences infertility. The most common cause of infertility in women is anovulation (no ovulation or release of eggs) brought about by irregularities in the hormones needed to produce and release healthy eggs.
Medical: Ovidrel is used to trigger ovulation in women with infertility due to anovulation and to promote final maturation of eggs in the ovaries of women undergoing assisted reproductive technologies (ART), such as in-vitro fertilization. Ovidrel is administered, usually self-administered by subcutaneous injection, after the stimulation of the growth of follicles or eggs in the ovaries of women being treated for infertility (e.g., see the Follitropin entries). In comparative trials versus an approved urine-derived hCG, Ovidrel was comparably effective and was associated with a lower incidence of injection site disorders.
hCG is useful for other treatments besides ART, e.g., male infertility, with some physicians using the product off-label for these indications:.
Market: The 2007 Average Wholesale Price (AWP) is $69.96 vial (unchanged from 2004) (Red Book, 2007), unchanged since at least 2005.
Ovidrel has a small market, e.g., sales were $17.7 million in 2004, and $12.4 million in 2003. The author’s guess for 2006 sales are on the order of $30 million.
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Companies involvement:
Full monograph
172 hCG, rDNA
Nomenclature:
hCG, rDNA [BIO]
Ovidrel [TR]
Ovitrelle [TR in Europe]
choriogonadotropin alfa [FDA INN]
chorionic gonadotropin, recombinant [SY]
human chorionic gonadotropin [SY]
rhCG [SY]
molecular weight (kDa) = 25.8
FDA Class: Drug NDA
Year of approval (FDA) = 2000
Date of 1st FDA approval = 20000927
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2017, based on 6,706,681 formulation patent; extension of 4,840,896 expired in 2009 |
U.S. Patent Expiration Year: | 2015 |
U.S. Biosimilars Data Exclusivity Expiration: | 2012 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2007 |
U.S. Biosimilars Launchability Year: | 2017 |
U.S. Biobetters Launchability Year: | 2017 |
Biosimilars/biobetters-related EU Patents: | 2006, based on EP 0211894, "FSH," and EP 0521586 |
EU Patent Expiration Year: | 2006 |
EU Biosimilars Data Exclusivity Expiration: | 2010 |
EU Biosimilars Orphan Exclusivity Expiration: | 2010 |
EU Biosimilars Launchability Year: | 2010 |
EU Biobetters Launchability Year: | 2006 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
hamster source materials
hormones
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
mammalian cell culture
lyophilized (freeze-dried)
NIH mouse potency test
phosphoric acid
sodium hydroxide
Sterile Water for Injection
sucrose
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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