Report on Corifollitropin Alfa (DB09066): A Sustained Follicle Stimulant for Reproductive Medicine

Section 1: Executive Summary

Corifollitropin alfa, marketed under the brand name Elonva, is a first-in-class, long-acting follicle-stimulating hormone (FSH) agonist developed through recombinant DNA technology for application in reproductive medicine.[1] As a biotech drug, its primary clinical innovation lies in its unique pharmacokinetic profile, which allows a single subcutaneous injection to initiate and sustain multifollicular growth for the first seven days of a Controlled Ovarian Stimulation (COS) cycle.[3] This offers a significant paradigm shift from conventional recombinant FSH (rFSH) therapies, which necessitate daily injections. The reduction in injection frequency directly addresses a major source of patient burden, stress, and potential for administration errors and non-compliance, which are well-documented challenges in Assisted Reproductive Technology (ART).[3]

The clinical development program for Corifollitropin alfa has produced robust evidence from large-scale, pivotal Phase III trials demonstrating its non-inferiority to daily rFSH regimens in terms of key efficacy endpoints, including ongoing pregnancy and live birth rates.[7] A consistent and statistically significant finding across these studies is a modest increase in the mean number of oocytes retrieved per cycle in patients treated with Corifollitropin alfa compared to daily rFSH.[1] The safety and tolerability profile of Corifollitropin alfa is comparable to that of established daily gonadotropins. The most significant clinical risk is Ovarian Hyperstimulation Syndrome (OHSS), a known class effect of all gonadotropins; however, its incidence with Corifollitropin alfa has been shown to be similar to that observed with standard-of-care daily rFSH protocols.[3]

The regulatory journey of Corifollitropin alfa highlights a notable divergence in global pharmaceutical oversight. The drug has received approval from the European Medicines Agency (EMA) and is currently marketed in over 75 countries, where it is an established therapeutic option within ART protocols.[12] In contrast, its path in the United States has been halted. In July 2014, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for the New Drug Application, and the drug remains unapproved for the U.S. market.[13] This complex regulatory landscape has defined its global availability and created a bifurcated standard of care. In summary, Corifollitropin alfa stands as a significant innovation in ART, offering a validated, patient-centric approach to ovarian stimulation with proven efficacy and a well-characterized safety profile, while its market presence continues to be shaped by differing international regulatory assessments.

Section 2: Molecular Profile and Mechanism of Sustained Action

2.1. A Novel Fusion Glycoprotein: Engineering for Longevity

Corifollitropin alfa is a complex dimeric glycoprotein, classified as a biotech drug and a fusion protein, that is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology.[3] The manufacturing process utilizes a chemically defined, protein-free cell culture medium, ensuring the final product is free of antibiotics and any proteins or components of human or animal origin.[4] Its molecular structure consists of two non-covalently linked subunits: a standard human alpha (

α)-subunit, which is structurally identical to the α-subunit found in native human FSH, luteinizing hormone (LH), and human chorionic gonadotropin (hCG), and a unique, chimeric beta (β)-subunit that is the key to its novel function.[1]

The defining feature of Corifollitropin alfa is this engineered β-subunit. It is a fusion protein meticulously constructed by linking the complete amino acid sequence of the human FSH β-subunit (residues 1-111) to the carboxy-terminal peptide (CTP) derived from the β-subunit of hCG (specifically, residues 118-145).[1] This bioengineering strategy was the culmination of research pioneered by Boime and his group, who sought to create a long-acting gonadotropin by leveraging the unique structural properties of hCG.[5]

The function of the appended CTP is the cornerstone of the drug's extended duration of action. The hCG-CTP contains four O-linked carbohydrate side chains, each terminating in sialic acid residues.[5] The addition of this heavily glycosylated peptide to the FSH

β-subunit significantly increases the overall molecular weight and negative charge of the Corifollitropin alfa molecule. This structural modification has a profound physiological consequence: it markedly reduces the rate of glomerular filtration and subsequent renal clearance.[5] By slowing its elimination from the body, the CTP dramatically prolongs the molecule's circulatory half-life compared to native or recombinant FSH, without altering its fundamental biological activity at the receptor level.[5] This direct causal chain—from the addition of the CTP to the reduction in renal clearance to the extension of the half-life—is the fundamental principle that enables the drug's clinical value proposition of less frequent dosing. The resulting molecule has a CAS Number of 195962-23-3 and an average protein molecular weight of 25398.0389 Da.[3]

Drug Profile Attribute	Detail	Source(s)
Generic Name	Corifollitropin alfa	3
Brand Name	Elonva	3
DrugBank ID	DB09066	3
Type	Biotech, Fusion Protein, Recombinant Glycoprotein	3
CAS Number	195962-23-3	20
Molecular Weight	25398.0389 Da	3
Originator	N.V. Organon (Netherlands)	16
Drug Class	Sustained Follicular Stimulant, Gonadotropin, FSH Receptor Agonist	1

2.2. Pharmacodynamics: Specific and Potent FSH Receptor Agonism

The pharmacodynamic activity of Corifollitropin alfa is characterized by its high specificity and potency as an agonist at the Follicle-Stimulating Hormone Receptor (FSHR).[1] Despite the incorporation of a peptide segment from hCG, a hormone known for its potent LH-like activity, Corifollitropin alfa has been specifically engineered to be devoid of any LH activity.[3] Its biological effects are therefore exclusively mediated through the FSHR signaling pathway, ensuring that its action is purely folliculogenic and does not induce premature luteinization.

In vitro studies have confirmed the high potency of Corifollitropin alfa, demonstrating a half-maximal effective concentration (EC50​) of 5.0 pM for FSHR activation.[15] This indicates a strong binding affinity and efficient signal transduction at the receptor, with a potency that is comparable to that of conventional recombinant FSH.[16]

The mechanism of action is consistent with that of endogenous FSH. In women, agonism at the FSHR on granulosa cells of the ovary initiates a cascade of events that leads to the recruitment of a cohort of antral follicles and sustains their subsequent growth and development.[1] This multifollicular development is the primary goal of COS in ART. In males, FSHR activation is essential for testicular growth and for supporting the process of spermatogenesis, specifically the maturation of sperm cells within the Sertoli cells of the seminiferous tubules.[12]

2.3. The Pharmacokinetic Basis for Weekly Dosing

The unique clinical utility of Corifollitropin alfa is entirely dependent on its distinct pharmacokinetic profile, which has been engineered for sustained action. Following a single subcutaneous injection, the drug exhibits a slower absorption profile compared to daily rFSH, which is attributed to its larger molecular size.[5] Maximum serum concentrations (

Cmax​) are achieved at a median time (Tmax​) of 44 hours (predicted range for 90% of subjects: 35-57 hours).[4] The absolute bioavailability after subcutaneous administration is approximately 58% (predicted range: 48-70%).[4]

Once absorbed, Corifollitropin alfa is distributed primarily to its target organs, the ovaries, as well as to the kidneys, which are the main site of its elimination.[3] The steady-state volume of distribution is 9.2 L.[3] Elimination occurs predominantly via renal clearance, with only a minor contribution from hepatic metabolism.[3] This reliance on renal elimination is a critical clinical consideration, as the rate of elimination may be significantly reduced in patients with renal insufficiency. Consequently, the use of Corifollitropin alfa is not recommended in this patient population.[2]

The cornerstone of the drug's pharmacology is its extended elimination half-life (t1/2​). Corifollitropin alfa has a mean t1/2​ of approximately 70 hours (predicted range: 59-82 hours), which is two to three times longer than the half-life of conventional rFSH.[4] This prolonged presence in the circulation ensures that serum FSH bioactivity remains above the therapeutic threshold required to sustain follicular growth for an entire week following a single dose.[4] This "sustained stimulant" profile, characterized by an initial peak of bioactivity followed by a slow decline, is fundamentally different from the "steady-state" profile achieved with daily rFSH injections, where concentrations are built up and maintained over several days.[19] This different follicular recruitment dynamic, potentially involving a larger initial cohort of follicles that undergo selection as FSH levels wane, may be the underlying mechanism for the consistently observed higher number of oocytes retrieved with Corifollitropin alfa compared to daily rFSH.

Pharmacokinetic analyses revealed that drug exposure, as measured by the area under the curve (AUC), increases in a linear, dose-proportional manner.[3] Critically, these studies also identified an inverse relationship between drug exposure and body weight; for a given dose, women with lower body weight achieve significantly higher serum concentrations than women with higher body weight.[5] This fundamental pharmacokinetic finding was pivotal, as it demonstrated that a single fixed dose for all patients would lead to a risk of overdosing (and increased OHSS risk) in lighter women and underdosing (and reduced efficacy) in heavier women. This understanding directly drove the clinical development of a weight-stratified dosing regimen (100 micrograms for women ≤60 kg and 150 micrograms for women >60 kg), a strategy essential for normalizing drug exposure and optimizing both the safety and efficacy of the therapy across diverse patient populations.[2]

Pharmacokinetic Parameter	Value (Mean and/or 90% Predicted Range)	Source(s)
Time to Max. Concentration (Tmax​)	44 hours (35 - 57 hours)	4
Max. Concentration (Cmax​)	4.24 ng/mL (2.49 - 7.21 ng/mL)	4
Absolute Bioavailability	58% (48 - 70%)	4
Volume of Distribution (Vd​)	9.2 L (6.5 - 13.1 L)	3
Elimination Half-life (t1/2​)	70 hours (59 - 82 hours)	4
Clearance (CL)	0.13 L/h (0.10 - 0.18 L/h)	4

Section 3: Clinical Application in Reproductive Medicine

3.1. Controlled Ovarian Stimulation (COS) in Assisted Reproductive Technology (ART)

The primary approved indication for Corifollitropin alfa is for Controlled Ovarian Stimulation (COS) to induce the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program, such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).[1] Critically, the indication specifies its use

in combination with a Gonadotropin-Releasing Hormone (GnRH) antagonist.[2] This partnership is not optional but mandatory from a pharmacological standpoint. The sustained, high level of stimulation provided by Corifollitropin alfa necessitates the rapid, on-demand suppression of the endogenous luteinizing hormone (LH) surge that only a GnRH antagonist can provide. The use of a GnRH agonist, which induces an initial flare of endogenous gonadotropins, is not recommended as it would be pharmacologically incompatible and could lead to an dangerously excessive ovarian response.[23] This highlights the co-evolution of stimulation and suppression agents in modern ART protocols.

The established treatment protocol is designed to maximize convenience while maintaining efficacy and safety:

• Stimulation Day 1: A single subcutaneous injection of Corifollitropin alfa is administered during the early follicular phase of the menstrual cycle (typically day 2 or 3).[21] This single dose is intended to replace the first seven daily injections of a conventional rFSH product.
• Stimulation Day 5 or 6: Treatment with a GnRH antagonist (e.g., ganirelix 0.25 mg) is initiated. The timing depends on the ovarian response, assessed by the number and size of growing follicles and/or serum estradiol levels. The antagonist prevents a premature LH surge and subsequent untimely ovulation, allowing the cohort of follicles to mature synchronously.[5]
• Stimulation Day 8 Onward: Seven days after the initial Corifollitropin alfa injection, the ovarian response is assessed. If further stimulation is required to meet the criteria for oocyte maturation, treatment is continued with daily injections of a conventional rFSH product (e.g., follitropin alfa or beta).[2] A typical daily dose is 150 IU, but this can be adjusted by the clinician based on the patient's response.[2] This part of the protocol is a pragmatic acknowledgment of biological variability; the drug's purpose is to replace the first seven injections, not necessarily the entire stimulation phase. This built-in flexibility allows physicians to tailor the latter part of the cycle to the individual patient's needs. In a significant portion of patients (32.8% in one study), the single injection of Corifollitropin alfa is sufficient to achieve adequate follicular development without the need for subsequent daily FSH, highlighting the potential for an even simpler regimen in ideal responders.[10]
• Triggering Final Oocyte Maturation: Once at least three follicles reach a diameter of 17 mm or more, a single injection of human Chorionic Gonadotropin (hCG; 5,000 to 10,000 IU) is administered to induce the final stages of oocyte maturation. Transvaginal ultrasound-guided oocyte retrieval is then scheduled approximately 34-36 hours after the hCG trigger.[2]

3.2. Treatment of Male Hypogonadotropic Hypogonadism

In addition to its primary use in female infertility, Corifollitropin alfa has a secondary indication for the treatment of hypogonadotropic hypogonadism in adolescent males aged 14 years and older.[12] This condition is characterized by deficient pituitary secretion of FSH and LH, leading to impaired testicular development, absent or delayed puberty, and azoospermia (absence of sperm).[12] The successful application in this context serves as a powerful validation of the drug's core biological function as a true, specific FSH analogue.

Treatment requires combination therapy with hCG, which acts as an LH analogue to stimulate testosterone production by Leydig cells.[12] Corifollitropin alfa provides the necessary FSH signal to promote the growth of seminiferous tubules and support spermatogenesis within the Sertoli cells.[21] The typical protocol involves a pre-treatment phase with hCG alone to normalize serum testosterone levels. For patients who remain azoospermic after this phase, Corifollitropin alfa is added to the regimen.[25] It is administered once every two weeks, in conjunction with twice-weekly hCG injections. This combined therapy may be continued for 52 weeks or longer to achieve full adult gonadal development and induce sperm production.[21] It is important to note that this therapy is ineffective in males with primary testicular failure, a condition identifiable by high baseline endogenous FSH levels, as the testes themselves are unable to respond to gonadotropin stimulation.[21]

3.3. Dosage, Administration, and Formulation

The dosing of Corifollitropin alfa is precisely tailored based on patient body weight to ensure optimal and safe drug exposure, a direct consequence of the pharmacokinetic findings.

• Female Dosing for COS (Weight-Based):
• For women with a body weight less than or equal to 60 kilograms: A single dose of 100 micrograms is administered.[2]
• For women with a body weight greater than 60 kilograms: A single dose of 150 micrograms is administered.[2]
• Adolescent Male Dosing for Hypogonadotropic Hypogonadism (Weight-Based):
• For males weighing less than or equal to 60 kg: 100 micrograms administered once every two weeks.[23]
• For males weighing more than 60 kg: 150 micrograms administered once every two weeks.[23]

Corifollitropin alfa is administered via subcutaneous injection, with the abdominal wall being the preferred site.[21] It is supplied as a sterile, clear, and colorless aqueous solution in a pre-filled syringe containing 0.5 mL of the product.[4] The syringes are available in two strengths: 100 micrograms and 150 micrograms.[23] The product is formulated with several excipients, including sodium citrate, sucrose, polysorbate 20, and methionine, with hydrochloric acid and/or sodium hydroxide used for pH adjustment. It is considered essentially 'sodium-free'.[4] The syringe is designed for ease of use and safety, featuring an automatic safety system that retracts the needle after injection to prevent needlestick injuries. This design facilitates self-administration by the patient or their partner, provided they have received proper instruction from a physician.[21]

Section 4: A Critical Review of Clinical Efficacy

The clinical efficacy of Corifollitropin alfa has been rigorously evaluated in a comprehensive program of large, multicenter, randomized, double-blind clinical trials. These studies were designed to compare a single injection of Corifollitropin alfa against the standard-of-care regimen of seven consecutive daily injections of recombinant FSH (rFSH), primarily follitropin beta, within a GnRH antagonist protocol.

4.1. Analysis of Pivotal Phase III Trials (ENGAGE, ENSURE, PURSUE)

The evidence supporting the efficacy of Corifollitropin alfa is anchored by three pivotal Phase III trials: ENGAGE, ENSURE, and PURSUE. These trials systematically assessed the drug's performance across different patient populations defined by weight and age.[7]

A consistent finding across all major trials was a statistically significant, though modest, increase in the number of oocytes retrieved in the Corifollitropin alfa arms.

• The ENGAGE trial, which enrolled 1,506 normal-responder women weighing >60 kg, compared a 150 µg dose of Corifollitropin alfa against daily 200 IU rFSH. The mean number of oocytes retrieved per started cycle was 13.7 for the Corifollitropin alfa group versus 12.5 for the rFSH group, a significant difference.[7]
• The ENSURE trial focused on 396 normal-responder women weighing ≤60 kg, comparing a 100 µg dose of Corifollitropin alfa to daily 150 IU rFSH. This trial also showed a significantly higher oocyte yield: 13.3 versus 10.6 for rFSH.[9]
• The PURSUE trial investigated an older population of 1,390 women aged 35-42 years with a body weight ≥50 kg, comparing a 150 µg dose of Corifollitropin alfa against daily 300 IU rFSH. In this group, the number of oocytes retrieved was similar, with 10.7 for Corifollitropin alfa versus 10.3 for rFSH.[9]

The primary efficacy endpoints related to pregnancy were designed to establish non-inferiority, meaning the goal was to prove that Corifollitropin alfa was not clinically worse than the established daily rFSH therapy. This objective was successfully met.

• In the ENGAGE trial, the ongoing pregnancy rates per initiated cycle were nearly identical at 38.9% for Corifollitropin alfa and 38.1% for rFSH, confirming non-inferiority.[7]
• In the PURSUE trial, the vital pregnancy rate was 23.9% for Corifollitropin alfa versus 26.9% for rFSH. The estimated difference of -3.0% had a 95% confidence interval of -7.4% to 1.4%, which fell within the predefined non-inferiority margin, thus meeting the primary endpoint.[26]

Across these trials, the median duration of stimulation was consistently 9 days in both the Corifollitropin alfa and daily rFSH arms.[7] This indicates that, on average, patients receiving the single Corifollitropin alfa injection required only two additional days of stimulation with daily rFSH before being ready for the hCG trigger. This confirms the drug's ability to effectively cover the first seven days of stimulation. The success of these trials was not in demonstrating superiority in pregnancy outcomes, but in proving that a much more convenient, patient-friendly regimen was "not worse" than the burdensome daily injection standard. This achievement is a major clinical victory, validating the drug's core value proposition.

Pivotal Phase III Trial	Patient Population	Corifollitropin Alfa Arm	Comparator Arm (Daily rFSH)	N	Mean Oocytes Retrieved (CFA vs rFSH)	Ongoing/Vital Pregnancy Rate (CFA vs rFSH)	Source(s)
ENGAGE	Normal responders, 18-36 yrs, >60 kg	150 µg (n=756)	200 IU Follitropin beta (n=750)	1506	13.7 vs 12.5	38.9% vs 38.1% (Ongoing)	7
ENSURE	Normal responders, 18-36 yrs, ≤60 kg	100 µg (n=268)	150 IU Follitropin beta (n=128)	396	13.3 vs 10.6	Not powered for pregnancy rates	9
PURSUE	Older patients, 35-42 yrs, ≥50 kg	150 µg (n=694)	300 IU Follitropin beta (n=696)	1390	10.7 vs 10.3	23.9% vs 26.9% (Vital)	9

4.2. Efficacy in Specific Patient Populations

Beyond the main pivotal trials, further studies have explored the efficacy of Corifollitropin alfa in specific and often more challenging patient subgroups.

• Older Women (35-42 years): The PURSUE trial and a separate randomized controlled trial conducted in a Vietnamese population specifically addressed this demographic.[26] Both studies confirmed that Corifollitropin alfa was equivalent to high-dose daily rFSH in terms of oocyte yield and crucial outcomes like ongoing pregnancy and live birth rates. These findings are vital as they establish the drug's utility in an increasingly common patient group in ART clinics.
• Poor Ovarian Responders: The evidence in this population is more nuanced. A randomized trial in patients meeting the "Bologna criteria" for poor ovarian response found no significant difference in ongoing pregnancy rates between a Corifollitropin alfa-based protocol and a daily rFSH protocol. However, it did report that significantly more patients in the Corifollitropin alfa group had supernumerary embryos available for cryopreservation, which could be a clinically relevant secondary benefit.[30] Another study in poor responders concluded that while neither treatment was superior, they could be used interchangeably.[31] This suggests that Corifollitropin alfa is a viable option, but perhaps not a breakthrough solution, for this difficult-to-treat population.
• High Responders: Women with conditions like Polycystic Ovarian Syndrome (PCOS) are considered high responders and are at an elevated risk for OHSS. A clinical trial (NCT02471677) was specifically designed to evaluate Corifollitropin alfa in this group, underscoring the need for caution and specialized protocols (such as using a GnRH agonist to trigger final maturation instead of hCG) to manage the risk of over-response.[32]
• Asian Patients: A trial in 400 Vietnamese women aged 35-42 confirmed the equivalence of Corifollitropin alfa to follitropin beta, adding to the body of evidence supporting its use in diverse global populations.[28] Incidental findings in another trial suggested that Asian poor responders might have different baseline characteristics and better prognoses than European poor responders, highlighting the importance of considering ethnicity in reproductive medicine research.[30]

4.3. Meta-Analytic Conclusions on Efficacy

To obtain the most robust conclusions, data from multiple trials have been pooled and analyzed in several meta-analyses. The most definitive of these is an Individual Patient Data (IPD) meta-analysis that included 3,292 patients from the ENGAGE, ENSURE, and PURSUE trials.[9] This high-level analysis confirmed that treatment with Corifollitropin alfa resulted in, on average, 1.0 more oocyte retrieved compared to daily rFSH (95% CI: 0.5-1.5). This statistically robust finding, however, did not translate into a statistically significant increase in pregnancy or live birth rates. The analysis confirmed non-inferiority, with the estimated difference for live birth rate being -2.0%, and a 95% confidence interval (-5.0% to 1.1%) that narrowly included the possibility of no difference or a slight disadvantage.[9] This raises a nuanced point: while more oocytes are retrieved, the marginal gain of one oocyte may not be sufficient to significantly alter the probability of achieving a live birth in a large population, though it could be profoundly important for an individual patient.

Other systematic reviews and meta-analyses have consistently supported these findings, concluding that Corifollitropin alfa is as efficient and effective as daily rFSH with respect to ongoing pregnancy and live birth rates in both normal and poor responder populations.[7]

While clinical efficacy is equivalent, economic considerations present a more complex picture. A cost-effectiveness analysis conducted from the patient's perspective in the Vietnamese trial of older women found that the total cost per patient was higher for the Corifollitropin alfa strategy (€4293) compared to the follitropin beta strategy (€4086). Consequently, the cost per live birth was also higher (€13,726 vs €12,511, respectively), leading to the conclusion that daily follitropin beta was the more cost-effective option in that setting.[36] This finding underscores that even for a clinically effective and more convenient drug, higher costs can be a significant barrier to adoption, particularly in healthcare systems where patients bear a large portion of the financial burden.

Section 5: Comprehensive Safety and Tolerability Profile

The safety and tolerability of Corifollitropin alfa have been extensively evaluated throughout its clinical development. The overall conclusion from multiple large-scale trials and pooled analyses is that its safety profile is reassuringly similar to that of conventional daily rFSH and is consistent with the known risks of gonadotropin therapy and the ART process itself.[7]

5.1. Common and Serious Adverse Events

The most frequently reported adverse events associated with Corifollitropin alfa are those commonly seen during ovarian stimulation. These events, typically occurring in 1% to 10% of patients, include headache, nausea, fatigue, pelvic pain or discomfort, and breast tenderness.[3] The overall incidence of drug-related adverse events is comparable to daily rFSH regimens. For instance, one analysis reported such events in 20.5% of women treated with Corifollitropin alfa versus 18.5% for rFSH, a difference that was not clinically significant.[27]

While generally well-tolerated, rare but serious adverse events have been reported. These are class effects associated with all gonadotropins and include severe thromboembolic events (blood clots), which can lead to reduced blood flow to vital organs.[23] Patients with recognized risk factors for thrombosis (e.g., personal or family history, severe obesity, thrombophilia) may have an increased risk when undergoing treatment.[23] Other rare, serious events reported in post-marketing surveillance or clinical trials include severe nervous system reactions (e.g., muscle stiffness, high fever, confusion) and serious eye symptoms (e.g., blurred vision, tunnel vision).[21]

5.2. Ovarian Hyperstimulation Syndrome (OHSS): A Key Consideration

Ovarian Hyperstimulation Syndrome (OHSS) is the most clinically significant complication of COS and is a primary safety concern for all gonadotropin therapies. It is a medical event distinct from uncomplicated ovarian enlargement and can range from mild symptoms (abdominal pain, nausea, diarrhea) to severe, life-threatening conditions characterized by large ovarian cysts, ascites (fluid in the abdomen), pleural effusion (fluid around the lungs), electrolyte imbalances, and thrombosis.[3]

The incidence of OHSS with Corifollitropin alfa has been a focal point of safety assessments. Pooled analyses of the pivotal trials and subsequent meta-analyses have consistently shown that the overall risk of OHSS (all grades) is not statistically different between Corifollitropin alfa and daily rFSH.[7] A pooled analysis of the ENGAGE and ENSURE trials indicated a small, statistically insignificant elevation in the risk of severe OHSS (a difference of 0.5%).[7] The comprehensive IPD meta-analysis calculated an odds ratio for moderate-to-severe OHSS of 1.29; however, the 95% confidence interval (0.81-2.05) crossed 1.0, confirming the lack of a statistically significant difference.[9]

Despite the similar incidence rates, the long-acting nature of Corifollitropin alfa presents a unique clinical challenge. Once administered, the stimulation effect cannot be stopped or titrated down for seven days. This lack of "reversibility" or "coastability" in the first week contrasts with daily rFSH, where the dose can be immediately reduced or withheld at the first sign of an excessive response.[11] This pharmacological property represents a loss of a degree of clinical control and may create a higher psychological barrier for its use in patients perceived to be at risk of a high response. This nuance is likely a key factor in regulatory considerations, even in the absence of a statistically proven higher risk.

Prevention of OHSS is paramount. Risk mitigation strategies include strict adherence to the recommended weight-based dosing, careful monitoring of ovarian response with ultrasound and estradiol levels, and pre-emptively withholding the hCG trigger if an excessive response (defined as >30 follicles ≥11 mm) is observed.[11]

Adverse Event	Corifollitropin Alfa	Daily rFSH	Odds Ratio (95% CI) / Comment	Source(s)
OHSS (All Grades)	1.7%	1.7%	In the PURSUE trial, incidence was identical.	26
Moderate-to-Severe OHSS	-	-	OR: 1.29 (0.81 - 2.05). Not statistically significant.	9
Pelvic Discomfort/Pain	Common (1-10%)	Common (1-10%)	One of the most frequently reported side effects.	3
Headache	Common (1-10%)	Common (1-10%)	Frequently reported in both treatment arms.	3
Nausea	Common (1-10%)	Common (1-10%)	Common side effect, similar between groups.	3
Serious Adverse Events	0.4%	2.7%	Lower incidence reported in the PURSUE trial.	26

5.3. Immunogenicity and Other Clinical Risks

As a recombinant fusion protein containing elements from two different human hormones, there was a theoretical concern regarding the immunogenic potential of Corifollitropin alfa. This risk was specifically investigated in the TRUST trial, which monitored patients for up to three treatment cycles.[11] The results were conclusive: there was no evidence of the formation of neutralizing antibodies against Corifollitropin alfa or FSH, nor was there an increase in local or systemic hypersensitivity reactions.[1] The molecule is considered to have a very low immunogenic potential, a significant achievement for its protein engineering.[11]

Other clinical risks are consistent with the ART process itself:

• Ovarian Torsion: Twisting of the ovary has been reported following treatment with all gonadotropins, including Corifollitropin alfa. The risk may be heightened by conditions such as OHSS, pregnancy, or the presence of ovarian cysts.[23]
• Multiple and Ectopic Pregnancy: The risk of multiple pregnancy is inherent to ART and is primarily related to the number of embryos transferred, not the type of gonadotropin used. The incidence is similar to daily rFSH protocols. Similarly, the risk of ectopic pregnancy is elevated in infertile women undergoing ART, a factor related to the patient's underlying condition rather than the medication.[21]
• Carcinogenicity and Mutagenicity: Based on available data, Corifollitropin alfa is not classified as a carcinogen or mutagen. No ingredient is listed by IARC, OSHA, or NTP as a carcinogen.[37]

5.4. Contraindications and Special Precautions

The contraindications for Corifollitropin alfa are designed to ensure patient safety, particularly by de-risking the "un-titratable" first week of stimulation. The list of contraindications is a proactive risk management strategy tailored to the drug's unique pharmacology.

Absolute Contraindications include [23]:

• Tumors of the ovary, breast, uterus, pituitary, or hypothalamus.
• Primary ovarian failure.
• Abnormal vaginal bleeding of an undiagnosed cause.
• Conditions incompatible with pregnancy, such as certain uterine fibroids or malformations of the reproductive organs.
• Known risk factors for a high ovarian response and OHSS, such as a history of OHSS, Polycystic Ovarian Syndrome (PCOS), or a basal antral follicle count >20.

Special Precautions for use include [2]:

• Renal Insufficiency: Use is not recommended in patients with mild, moderate, or severe renal impairment, as the drug's elimination may be reduced, leading to prolonged and excessive exposure.
• GnRH Agonist Protocols: Use is not recommended in combination with a GnRH agonist due to the potential for an excessive and uncontrolled ovarian response.
• Single Injection Per Cycle: It is imperative that only one injection of Corifollitropin alfa is administered within the same treatment cycle. Additional injections would constitute an overdose and significantly increase the risk of OHSS.

Section 6: Comparative Analysis and Regulatory Landscape

Corifollitropin alfa's position in reproductive medicine is best understood through a direct comparison with its predecessor, daily recombinant FSH (rFSH), and an examination of its divergent regulatory journey across the globe.

6.1. Corifollitropin Alfa versus Daily rFSH: A Head-to-Head Comparison

The choice between Corifollitropin alfa and daily rFSH involves a trade-off between convenience, cost, and clinical control.

• Administration and Convenience: This is the most significant differentiator and the primary advantage of Corifollitropin alfa. A single injection replaces seven consecutive daily injections, drastically reducing the physical and psychological burden on the patient.[3] This simplification can reduce stress, minimize the potential for injection errors, and may improve treatment adherence. The successful marketing of the drug in over 75 countries, despite not offering superior pregnancy rates, is a testament to the high value that patients and clinicians place on this improved convenience.[13]
• Efficacy: The two treatment modalities are considered to have equivalent efficacy. Robust meta-analyses confirm the non-inferiority of Corifollitropin alfa for the most critical clinical endpoints of ongoing pregnancy and live birth rates.[7] Corifollitropin alfa does consistently yield a statistically significant but small increase in the number of total and mature (Metaphase II) oocytes retrieved.[18]
• Safety: The safety profiles are broadly similar. There are no statistically significant differences in the incidence of common adverse events or in the risk of the most serious complication, OHSS.[7]
• Control and Flexibility: Daily rFSH provides clinicians with maximum flexibility. The dose can be adjusted up or down, or stopped entirely ("coasting"), on any given day in response to the patient's follicular development and estradiol levels. Corifollitropin alfa, by its long-acting nature, commits the patient and clinician to a set level of stimulation for the first seven days, removing this option for fine-tuning during the critical initial phase of follicular recruitment.
• Cost: The economic aspect can be a deciding factor. At least one detailed cost-effectiveness analysis concluded that, from a patient's perspective in a specific setting, Corifollitropin alfa was less cost-effective than daily follitropin beta due to higher upfront drug costs, even with similar clinical outcomes.[36] This suggests that its adoption may be limited in healthcare systems or for patients where cost is a primary concern.

6.2. Global Regulatory Journey: EMA Approval and FDA Response

The regulatory history of Corifollitropin alfa is a compelling case study in the globalization of drug development and the fragmentation of regulatory approval.

• European Approval and Global Rollout: Following a positive assessment by the European Medicines Agency (EMA), Corifollitropin alfa, under the brand name Elonva, was granted marketing authorization by the European Commission on January 25, 2010.[2] This approval paved the way for its successful launch across the European Union and subsequently in over 75 countries worldwide, including markets in Asia like Singapore.[6] In these regions, it has become an established part of the standard of care in ART. It is noteworthy that some national bodies, such as the Scottish Medicines Consortium (SMC) for NHS Scotland, initially did not recommend its use, a decision based on the nature of the submission from the company at that time rather than a negative clinical assessment.[39]
• The U.S. FDA Trajectory and Complete Response Letter: The journey in the United States took a different course. Merck announced that its New Drug Application (NDA) for Corifollitropin alfa was accepted for standard review by the U.S. Food and Drug Administration (FDA) on September 9, 2013.[6] However, on July 29, 2014, Merck received a Complete Response Letter (CRL) from the FDA.[13] A CRL signifies that the agency has completed its review of the data package but has determined that it cannot approve the application in its current form. The specific deficiencies cited by the FDA in the CRL have not been made public, but Merck stated it was "evaluating the information provided".[13] As of the latest available information, Corifollitropin alfa remains unapproved for use in the United States.

This divergence in regulatory outcomes is profound. The EMA and dozens of other global health authorities reviewed the same core clinical data package from the ENGAGE, ENSURE, and PURSUE trials and concluded that the drug's benefit-risk profile was positive.[12] The FDA, reviewing the same evidence, reached a different conclusion. This suggests a fundamental difference in regulatory philosophy or risk tolerance. The FDA may have placed greater weight on the lack of titratability in the first week of stimulation and the non-significant numerical trend towards a higher odds ratio for OHSS.[9] For a drug positioned primarily as a "convenience" alternative rather than one addressing a life-threatening, unmet need, the FDA's threshold for any potential increase in risk may be exceptionally high. This regulatory decision has effectively bifurcated the global standard of care, making a routine treatment in Europe and Asia completely unavailable to patients in the United States.

Section 7: Synthesis and Concluding Remarks

Corifollitropin alfa stands as a significant and successful innovation in the pharmacology of Assisted Reproductive Technology. Its development represents a triumph of rational drug design, where an intelligent molecular modification—the fusion of the hCG-CTP to the FSH β-subunit—directly translated into a tangible clinical benefit: a marked reduction in patient treatment burden.

The primary strength of Corifollitropin alfa is its patient-centric protocol. The replacement of seven daily injections with a single, effective dose is a powerful value proposition that mitigates the significant stress, inconvenience, and potential for error associated with daily self-administration. This convenience is supported by a robust body of evidence from large-scale, well-controlled clinical trials that have unequivocally demonstrated its equivalent efficacy to the daily rFSH standard of care, as measured by the critical outcomes of ongoing pregnancy and live birth rates. Furthermore, it offers a small but consistent advantage in the number of oocytes retrieved per cycle. Its safety profile is well-characterized, manageable, and reassuringly similar to that of other gonadotropins, with no evidence of immunogenicity.

Despite these strengths, the drug has limitations and faces challenges. The most prominent pharmacological limitation is the inherent lack of dose flexibility during the first seven days of stimulation. This "un-titratable" period removes a degree of clinical control and necessitates careful patient selection to avoid an excessive response, a concern that likely weighs heavily in regulatory assessments. While the overall risk of OHSS is not statistically higher than with daily rFSH, the management of a developing over-response is less straightforward. From a practical standpoint, its higher acquisition cost in some healthcare markets may render it less cost-effective than daily alternatives, limiting its accessibility for many patients. The most significant challenge to its global reach has been its failure to gain FDA approval, which has prevented its use in the large U.S. market and created a notable divergence in international clinical practice.

In conclusion, Corifollitropin alfa is a valuable and validated tool in the armamentarium of the modern reproductive endocrinologist. It is an excellent option for appropriately selected patients, particularly normal responders who prioritize convenience and wish to minimize the emotional and physical burden of daily injections. Future research may further refine its use in specific populations, such as poor responders, and enhance predictive models to better identify ideal candidates who can benefit most from its unique pharmacokinetic profile. The ultimate place of Corifollitropin alfa in the U.S. market remains an open question, contingent on the resolution of the regulatory concerns that have, for now, defined its divided global legacy.

Works cited

1. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility. - DrugBank, accessed August 11, 2025, https://go.drugbank.com/articles/A32516
2. The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 22 September 2010 ELONVA 100 μg/0.5 ml,, accessed August 11, 2025, https://www.has-sante.fr/jcms/c_1261511/fr/elonva-ct-8390-version-anglaise
3. Corifollitropin alfa: Uses, Interactions, Mechanism of Action ..., accessed August 11, 2025, https://go.drugbank.com/drugs/DB09066
4. PRODUCT INFORMATION - E-lactancia, accessed August 11, 2025, https://www.e-lactancia.org/media/papers/CorifollitropinElonva-DS-MSD2017.pdf
5. The role of corifollitropin alfa in controlled ovarian stimulation for IVF ..., accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3163654/
6. corifollitropin alfa - New Drug Approvals, accessed August 11, 2025, https://newdrugapprovals.org/tag/corifollitropin-alfa/
7. Corifollitropin Alfa for Controlled Ovarian Stimulation in Assisted Reproductive Technologies: State of the Art - PMC, accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10021006/
8. Corifollitropin alfa: a review of its use in controlled ovarian stimulation for assisted reproduction - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/21815699/
9. Corifollitropin alfa versus recombinant follicle-stimulating hormone ..., accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/27178762/
10. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/20483664/
11. Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity - PMC, accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3137390/
12. Elonva | European Medicines Agency (EMA), accessed August 11, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/elonva
13. Corifollitropin alfa: What is it and is it FDA approved? - Drugs.com, accessed August 11, 2025, https://www.drugs.com/history/corifollitropin-alfa.html
14. Merck Announces FDA Acceptance of New Drug Application for Investigational Fertility Treatment, accessed August 11, 2025, https://www.merck.com/news/merck-announces-fda-acceptance-of-new-drug-application-for-investigational-fertility-treatment/
15. Corifollitropin alfa (Org 36286) | FSH Receptor Agonist | MedChemExpress, accessed August 11, 2025, https://www.medchemexpress.com/corifollitropin-alfa.html
16. Corifollitropin alfa CAS#: 195962-23-3 - ChemicalBook, accessed August 11, 2025, https://m.chemicalbook.com/ProductChemicalPropertiesCB13143781_EN.htm
17. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/19337959/
18. Corifollitropin Alfa Compared to Daily Recombinant FSH in in Vitro Fertilization Programmes: A Meta-Analysis of Randomized-Controlled Trials - IMR Press, accessed August 11, 2025, https://www.imrpress.com/journal/CEOG/50/2/10.31083/j.ceog5002042/htm
19. Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation - PMC, accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4917789/
20. 195962-23-3 | CAS DataBase - ChemicalBook, accessed August 11, 2025, https://m.chemicalbook.com/CASEN_195962-23-3.htm
21. Corifollitropin Alfa: Uses, Side Effects, Dosage - MedicineNet, accessed August 11, 2025, https://www.medicinenet.com/corifollitropin_alfa/article.htm
22. Corifollitropin alfa (Org 36286; MK-8962) | CAS 195962-23-3 | AbMole BioScience, accessed August 11, 2025, https://www.abmole.com/products/corifollitropin-alfa.html
23. Elonva, INN-corifollitropin alfa - EMA, accessed August 11, 2025, https://www.ema.europa.eu/en/documents/product-information/elonva-epar-product-information_en.pdf
24. Elonva - NPS MedicineWise, accessed August 11, 2025, https://www.nps.org.au/medicine-finder/elonva-solution-for-injection
25. An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/28270212/
26. Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/26003273/
27. Investigational fertility treatment approved by FDA - Contemporary OB/GYN, accessed August 11, 2025, https://www.contemporaryobgyn.net/view/investigational-fertility-treatment-approved-fda
28. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35-42 years with a body weight ≥50 kg - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/30895237/
29. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35–42 years with a body weight ≥50 kg, accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6276648/
30. Corifollitropin alfa followed by highly purified HMG versus recombinant FSH in young poor ovarian responders: a multicentre randomized controlled clinical trial - PubMed, accessed August 11, 2025, https://pubmed.ncbi.nlm.nih.gov/29040589/
31. Comparing Corifollitropin Alfa to Recombinant Follicle-STIMULATING Hormone in Poor Responder Patients Undergoing Intracytoplasmic Injection: A Randomized Clinical Trial - Crescent Journal of Medical and Biological Sciences, accessed August 11, 2025, https://www.cjmb.org/text.php?id=643
32. Corifollitropin Alfa Versus Follitropin Beta in High Responders - ClinicalTrials.gov, accessed August 11, 2025, https://clinicaltrials.gov/study/NCT02471677
33. Study Details | Corifollitropin Alfa Versus Follitropin Beta in High Responders | ClinicalTrials.gov, accessed August 11, 2025, https://clinicaltrials.gov/study/NCT02471677?cond=Corifollitropin%20alfa&viewType=Table&rank=3
34. Corifollitropin alfa versus recombinant follicle-stimulating hormone: An individual patient data meta-analysis | Request PDF - ResearchGate, accessed August 11, 2025, https://www.researchgate.net/publication/301760962_Corifollitropin_alfa_versus_recombinant_follicle-stimulating_hormone_An_individual_patient_data_meta-analysis
35. Corifollitropin Alfa Compared to Daily Recombinant FSH in in Vitro Fertilization Programmes: A Meta-Analysis of Randomized-Controlled Trials - IMR Press, accessed August 11, 2025, https://www.imrpress.com/journal/CEOG/50/2/10.31083/j.ceog5002042
36. Corifollitropin alfa versus follitropin beta: an economic analysis alongside a randomized controlled trial in women undergoing IVF/ICSI, accessed August 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7235613/
37. Corifollitropin Alfa Formulation - Organon, accessed August 11, 2025, https://www.organon.com/docs/product/safety-data-sheets/Corifollitropin%20Alfa%20Formulation_HH_US_EN.pdf
38. Corifollitropin Alfa Compared to Daily Recombinant FSH ... - IMR Press, accessed August 11, 2025, https://article.imrpress.com/journal/CEOG/50/2/10.31083/j.ceog5002042/f60d7ada14db3cd3f99d42c308595f76.pdf
39. corifollitropin alfa (Elonva) - Scottish Medicines Consortium, accessed August 11, 2025, https://scottishmedicines.org.uk/medicines-advice/corifollitropin-alfa-elonva-nonsubmission-63310/