Status: MAA approved in EU in Jan. 2010; BLA pending

Organizations involved:

Merck & Co., Inc. – Manuf.; R&D; Tech.; Intl. mark.; Parent

Organon Teknika B.V. – Former

Schering-Plough Corp. – Parent; Former

Washington University – R&D; Tech.

Modigene Inc. – Tech.

Cross ref. See the Follicle-stimulating Hormone (FSH) Products entry (#154).     

Description: Corifollitropin alfa (FSH-CTP) is a long-acting follicle-stimulating hormone (FSH) mutein or variant recombinant fusion glycoprotein composed of the FSH alpha subunit linked to a hybrid beta FSH subunit composed of an oligosaccharide-extended (glycosylated) C(arboxy)-terminal peptide (CTP; amino acids 118-145) portion of the beta subunit of human chorionic gonadotrophin (HCG) appended to the C-terminus of the beta subunit of human FSH, expressed by transformed Chinese hamster ovary (CHO) cells. It may also be considered as human FSH heterodimer modified with an appended CTP. FSH-CTP is expressed by CHO cells transfected with linked/fused genes encoding the alpha- and beta-subunits of human FSH and the CTP part of hCG. FSH-CTP has ten glycosylation sites.

Nomenclature: Corifollitropin alfa, rDNA [BIO]; corifollitropin alfa [INN CAS]; Elonva [TR]; follicle-stimulating hormone (human alpha-subunit reduced), complex with folliclestimulating hormone (human beta]-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human beta-subunit) [CAS]; Org 36286 [SY]; follicle stimulating hormone-C-terminal peptide (CTP) [SY]; FSH-CTP [SY]; sustained follicular stimulant [SY]; SFS [SY]

Note, the “alfa” in the INN iindicates modified glycosylation, not order of discovery or importance.

Biological.: Corifollitropin alfa was designed to provide controlled ovarian stimulation to induce the development of multiple follicles in patients participating in an assisted reproductive technology program. As discussed in the Follicle-Stimulating Hormone (FSH) Products entry (see #154), FSH is a pituitary glycoprotein hormone essential for follicular growth in females and for spermatogenesis in males.

FSH belongs, along with leutenizing hormone (LH), human chorionic gonadotrophin (HCG), and thyroid-stimulating hormone (TSH), to a family of glycoproteins which are heterodimers with two subunits -- alpha and beta. The alpha-subunits of all of these hormones are identical, while the beta-subunits are hormone-specific and determine biological specificity. The beta-subunit of hCG is distinct from the others due to an extension of the C-terminus portion (C-terminal peptide; CTP) with four O-linked oligosaccharides, i.e., it has modified glycosylation. This extension results in a prolonged in vivo half-life. Site-directed mutagenesis and gene transfer techniques were used to develop FSH-CTP.

CTP is a small peptide naturally found in the body as a portion of the protein hCG, a female hormone that helps maintain pregnancy has a much longer life-span than that of the hormone LH, which assists in helping females get pregnant and males to produce testosterone, and is identical to hCG except for the CTP portion. hCG is a natural part of the female system, and males are exposed to it during the 9-month pregnancy period. Therefore, CTP has strong potential to be non-toxic and non-immunogenic to humans when attached to other proteins, and is useful for prolonging the life-span of many hormones, enzymes and peptides. CTP can be readily attached to a wide array of therapeutic proteins, stabilizing the therapeutic protein in the bloodstream and greatly extending its life span without additional toxicity or loss of desired biological activity. CTP-modified proteins can be manufactured using established recombinant DNA techniques in widely used mammalian protein expression systems

FSH is used for treatment of both female and male infertility. Protocols for the induction of follicular development in women and spermatogenesis in men commonly rely on multiple injections of FSH preparations. The availability of longer-acting FSH would allow the development of new, more convenient treatment regimens. FSH-CTP has been shown to be a potent inducer of multiple follicular growth, including prior to in vitro fertilisation (IVF) or intracytoplasmic sperm injection.

Corifollitropin alfa is the first in a new class of long-acting fertility hormones called ‘Sustained Follicle Stimulants’ (SFS). The primary advantage of an SFS over current gonadotropins is longer duration of action, which allows a treatment regimen replacing 7 daily injections of current gonadotropins with one injection of corifollitropin alfa.

Elonva is used for controlled ovarian stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an assisted reproductive technology (ART) program. Elonva is designed as a sustained follicle stimulant with the same pharmacodynamic profile as rFSH, but with a markedly prolonged duration of FSH activity.

Companies.: Corifollitropin alfa was developed and is manufactured by Organon Teknika B.V., which was acquired by Schering-Plough Corp. in March 2007. It will be marketed worldwide by Organon and affiliates, e.g., Organon USA Inc. in the U.S. The molecule and related technology have been exclusively licensed from Washington University (see the Tech. transfer section below).

In Nov. 2009, Merck & Co., Inc. acquired Schering-Plough in a deal valued at over $41 billion.

Status: Organon filed an MAA for European Union (EU) approval on Dec. 31. 2008, followed by a planned BLA filing in the U.S. Organon filed for approval of a single injection of 100 µg injection of corifollitropin alfa to induce multifollicular development for controlled ovarian stimulation (COS) as part of in vitro fertilization and/or intracytoplasmic sperm injection procedures.

On Jan. 28, 2010, EMEA/EU approved Elonva for controlled ovarian stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an assisted reproductive technology (ART) program.

Tech. transfer: CTP technology and FSH-CTP were originally developed by Dr. I. Boime, Washington University School of Medicine, and FSH-CTP and related inventions were exclusively licensed to Organon. Related U.S. patents assigned to the university include 5,338,835, a division of 5,177,193, “CTP-extended form of FSH,” with an exemplary claim (#1), “An extended human FSH subunit wherein the amino acid sequence of a carboxy terminal peptide (CTP) representing positions from about 112-118 to 145 of the human chorionic gonadotrophin beta subunit is appended to the C-terminal amino acid residue at position 111 of a wild-type human FSH beta subunit.” The pM2/alpha vector is used for expression of these dimeric hormones of this family. This is particularly claimed in U.S. 5,405,945, “DNA encoding reproductive hormones and expression using a minigene,” also a division of 5,177,193. This “minigene” is characterized by retention only of the intron sequence between exon III and exon IV, all upstream introns having been deleted. There are a number of related divisions and continuations of 5,177,193, but this family of patents has expired, with 5,177,193 expiring in 2010.

The scientific founder of Modigene, Dr. Fuad Fares, was a post-doctoral student of Prof. Boime. Dr. Fares formed ModigeneTech and licensed the CTP technology from Washington University for all therapeutic Indications: other than those previously licensed by Schering-Plough -- use with LH, FSH, TSH and hCG.

In July 2011, PROLOR Biotech received a notice of allowance of a U.S. patent application covering the company's CTP platform. The allowed claims cover CTP-modified compositions of a wide array of classes of therapeutic proteins, including hormones, high affinity protein ligands, proteins that induce or regulate an immune response, proteins that are involved with autocrine and paracrine activities, and mimetics of these therapeutic proteins, as well as other types of proteins. This apparently refers to U.S. 8,114,836, "Long-acting veterinary polypeptides and methods of producing and administering same," with calculated expiration date of Feb 5, 2027. Note, despite "veterinary" in the title, as noted in the abstract, "methods of using both human and non-human polypeptides and polynucleotides are also disclosed."

U.S. 6635256, "Glycoprotein hormone compositions comprising two β subunits and methods of use thereof," and 7,442,376, with the same title, both assigned to Washington University, have calculated expiration dates of Oct 19, 2018.

Trials: In its trials, a single dose of FSH-CTP has been shown to be able to initiate and sustain multifollicular growth for up to an entire week, replacing the need for daily fertility hormone (FSH) injections during this period.

The LIFE program is Organon’s clinical development program for corifollitropin alfa for the therapeutic indication of controlled ovarian stimulation. The most important trials in this program are ENGAGE, a Phase III efficacy and safety study with corifollitropin alfa 150 µg;, ENSURE, a Phase III efficacy and safety study in women ≤60 kg with corifollitropin alfa 100 µg; and TRUST, a Phase III safety study of repeated treatment.

In June 2007, Organon reported that two out of three Phase III clinical trials with corifollitropin alfa had reached their randomization target. The ENGAGE trial, the largest double-blind fertility trial ever performed, is seeking to demonstrate efficacy and safety of corifollitropin alfa 150 µg in a double-blind comparison with Organon’s Puregon (conventional FSH; see related entry), one of the most commonly used preparations to treat infertile patients. The recruitment goal was to include a total of 1,400 patients from 34 fertility clinics in Europe, USA and Canada. The trial started in July, 2006.

A second trial, ENSURE, is an efficacy and safety trial with corifollitropin alfa 100 µg designed specifically for women who weigh less than 60 kg (133 lbs). This double-blind study comparing corifollitropin alfa with Puregon was started in Jan. 2007 in 19 clinical trial centers in Europe and Asia. All 330 subjects have now been randomized.

A third Phase III trial in the LIFE program (the TRUST trial) focuses on safety of repeated treatments with corifollitropin alfa, and is expected to complete recruitment by mid-August 2007.

In the final results from the ENGAGE trial, the ongoing pregnancy rate, the primary endpoint, obtained in the Elonva treatment arm (38.9% per started cycle) was similar to that achieved in patients receiving a daily dose of rFSH (38.1% per started cycle). Engage was a non-inferiority trial designed to compare Elonva 150 mcg to 200 IU rFSH. A total of 1,506 patients (with a body weight greater than 60 kg) at 34 in-vitro fertilization (IVF) clinics in North America and Europe were randomized to start stimulation with either Elonva 150 mcg or a daily dose of 200 IU rFSH for seven days. Patients also received rFSH (maximum 200 IU/day) from stimulation day eight onward, when required. Starting on stimulation day five, all patients received 0.25mg gonadotropin-releasing hormone (GnRH) antagonist until triggering of final oocyte maturation by human chorionic gonadotropin (hCG). The primary endpoint was the ongoing pregnancy rate assessed at ten weeks or more after embryo transfer. In the Elonva treatment arm, the ongoing pregnancy rate (38.9% per started cycle) was similar to that achieved in patients receiving a daily dose of rFSH (38.1% per started cycle). The number of oocytes retrieved per attempt, the co-primary endpoint, was 13.7 (+/- 8.2) for the Elonva group and 12.5 (+/- 6.7) for the rFSH group.

Medical: Elonva is the first sustained follicle stimulant. Due to its ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose may replace the first seven injections of any conventional daily recombinant follicle stimulating hormone (rFSH) preparation in a COS treatment cycle. A single dose of FSH-CTP is able to initiate and sustain multifollicular growth for up to an entire week, replacing the need for daily fertility hormone injections, e.g., Puregon or other recombinant FSH product, during this period.

Market: FSH-CTP is currently primarily intended for use in women undergoing controlled ovarian stimulation (COS) during infertility treatment. Worldwide, over 700,000 cycles using COS for assisted reproduction treatment for in vitro fertilization and/or intracytoplasmic sperm injection take place each year. See also the other entries used for infertility treatment for further market information.

With its improved pharmacokinetic and dynamic profile, FSH-CTP offers more convenient regimens for the treatment of infertility. In a survey sponsored by Organon, 91% of the infertility experts questioned stated that they expect their patients to be positive about this new treatment regimen.

R&D: PROLOR Biotech, Inc. is also a license of Washington Univ., with the exclusive license to apply CTP to all non-fertility-realted therapeutic proteins and peptides.