Corifollitropin alfa

Identification

Name
Corifollitropin alfa
Accession Number
DB09066
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Corifollitropin alfa, also known as Elonva is used in women undergoing fertility treatment to stimulate the development of more than one mature egg (oocyte) at a time in the ovaries. This drug used together with a gonadotropin-releasing hormone (GnRH) antagonist, a type of medicine also used in fertility treatments. Elonva is available only by prescription [6].

In July 2014, Merck announced the receipt of a Complete Response Letter (CRL) from the U.S. FDA for its New Drug Application for this drug. Corifollitropin alfa is marketed as Elonva in more than 75 countries [8].

Corifollitropin alfa is produced by a method known as ‘recombinant DNA technology’. This means that it is made by cells into which a DNA has been introduced that makes them able to produce corifollitropin alfa [6].

Multiple studies and a meta-analysis suggest that corifollitropin alfa is as efficacious as recombinant FSH in terms of live birth rate, ongoing pregnancy rate, as well as clinical pregnancy rate. The increased in the number of eggs retrieved under corifollitropin alfa regimen represents the elevated effectiveness of this drug, however, warns at the same time against the possibility of an increased risk of ovarian hyperstimulation in the high responder study group of women [12], [4].

Protein chemical formula
Not Available
Protein average weight
25398.0389 Da
Sequences
Not Available
Synonyms
  • FSH-CTP
External IDs
MK-8962 / ORG 36286 / ORG-36286 / SCH 900962 / SCH-900962
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ElonvaInjection, solution100 microgramsSubcutaneousMerck Sharp & Dohme Limited2010-01-25Not applicableEu
ElonvaInjection, solution150 microgramsSubcutaneousMerck Sharp & Dohme Limited2010-01-25Not applicableEu
International/Other Brands
Elonva (Merck)
Categories
UNII
T7K20Y2GWY
CAS number
195962-23-3

Pharmacology

Indication

Controlled ovarian stimulation [9] in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments)[6].

Pharmacodynamics

A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection [10].

This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines [6].

In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment [10].

Mechanism of action

Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit) [6]. Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance [13].

The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH [1].

Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG) [7]. This unit interacts with the FSH receptor [1] to stimulate the release of oocytes.

Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity [6].

TargetActionsOrganism
AFollicle-stimulating hormone receptor
agonist
Human
Absorption

After one single subcutaneous injection of this drug, the maximal serum concentration is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%) [6].

Volume of distribution

Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH [9].

After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9.2 L [9].

Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms [6].

Protein binding
Not Available
Metabolism

The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism [3].

Route of elimination

Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part) [3].

Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa [6].

Half life

Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing [1].

Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours) [6].

Clearance

0.13 L/h (0.10-0.18 L/h1) [6]

Toxicity

The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea [6].

More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome [6], which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg [11].

In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur [11]. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death [6].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Corifollitropin alfa which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineCorifollitropin alfa may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Corifollitropin alfa which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Loutradis D, Drakakis P, Vlismas A, Antsaklis A: Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility. Curr Opin Investig Drugs. 2009 Apr;10(4):372-80. [PubMed:19337959]
  2. de Lartigue J: Corifollitropin alfa: a new option to treat female infertility. Drugs Today (Barc). 2011 Aug;47(8):583-90. doi: 10.1358/dot.2011.47.8.1635872. [PubMed:21850281]
  3. van Schanke A, van de Wetering-Krebbers SF, Bos E, Sloot WN: Absorption, distribution, metabolism and excretion of corifollitropin alfa, a recombinant hormone with a sustained follicle-stimulating activity. Pharmacology. 2010;85(2):77-87. doi: 10.1159/000276546. Epub 2010 Jan 21. [PubMed:20110752]
  4. Benchabane M, Santulli P, Maignien C, Bourdon M, De Ziegler D, Chapron C, Gayet V: [Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for oocyte donors]. Gynecol Obstet Fertil Senol. 2017 Feb;45(2):83-88. doi: 10.1016/j.gofs.2016.12.022. Epub 2017 Feb 16. [PubMed:28368800]
  5. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35–42 years with a body weight ≥50 kg: a randomized controlled trial [Link]
  6. EMA label [Link]
  7. Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation [Link]
  8. Corifollitropin alfa approval [Link]
  9. Australian APA report document, corifollitropin alfa [Link]
  10. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility. [Link]
  11. Ovarian hyperstimulation syndrome [Link]
  12. Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis [Link]
  13. Gonadotrophins: The future [Link]
External Links
Wikipedia
Gonadotropin_preparations
ATC Codes
G03GA09 — Corifollitropin alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentInfertilities1
1, 2CompletedTreatmentInfertilities1
2CompletedTreatmentAssisted Reproductive Technology therapy1
2CompletedTreatmentAssisted Reproductive Technology therapy / Infertilities1
2CompletedTreatmentFertilization1
2CompletedTreatmentInfertilities1
2CompletedTreatmentInfertilities / Poor Ovarian Response2
2TerminatedTreatmentOvulation induction therapy1
3CompletedOtherInfertilities1
3CompletedTreatmentAssisted Reproductive Technology therapy2
3CompletedTreatmentHypogonadism / Idiopathic Hypogonadotropic Hypogonadism1
3CompletedTreatmentInfertilities3
3CompletedTreatmentInfertilities / Poor Ovarian Response1
3RecruitingTreatmentIdiopathic Hypogonadotropic Hypogonadism1
3RecruitingTreatmentInfertility, Female / Polycystic Ovaries Syndrome1
3WithdrawnTreatmentInfertilities1
4CompletedTreatmentInfertilities3
4CompletedTreatmentOocyte Donation1
4CompletedTreatmentSubfertility1
4Not Yet RecruitingTreatmentBMI >30 kg/m21
4Not Yet RecruitingTreatmentInfertilities2
4RecruitingTreatmentInfertility, Female1
4TerminatedTreatmentInfertilities1
4Unknown StatusTreatmentAssisted Reproductive Technology therapy1
4Unknown StatusTreatmentFemale Reproductive Problem / Infertilities1
4WithdrawnTreatmentInfertilities1
Not AvailableCompletedNot AvailableAssisted Reproductive Technology therapy2
Not AvailableCompletedNot AvailableInfertility, Female1
Not AvailableCompletedNot AvailableInfertility, Subfertility1
Not AvailableCompletedNot AvailableNeonates / Pregnancy6
Not AvailableCompletedNot AvailablePregnancy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous100 micrograms
Injection, solutionSubcutaneous150 micrograms
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled peptide receptor activity
Specific Function
Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Induces cAMP production through the activation of PI3K-AKT and S...
Gene Name
FSHR
Uniprot ID
P23945
Uniprot Name
Follicle-stimulating hormone receptor
Molecular Weight
78264.07 Da
References
  1. Loutradis D, Drakakis P, Vlismas A, Antsaklis A: Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility. Curr Opin Investig Drugs. 2009 Apr;10(4):372-80. [PubMed:19337959]
  2. de Lartigue J: Corifollitropin alfa: a new option to treat female infertility. Drugs Today (Barc). 2011 Aug;47(8):583-90. doi: 10.1358/dot.2011.47.8.1635872. [PubMed:21850281]

Drug created on May 11, 2015 16:42 / Updated on August 02, 2018 06:13