Follitropin Delta (Rekovelle®): A Comprehensive Pharmacological and Clinical Review of a Novel Recombinant Gonadotropin with an Individualized Dosing Algorithm

I. Executive Summary

Follitropin delta, marketed under the brand name Rekovelle®, represents a significant advancement in the field of reproductive medicine, specifically in the domain of controlled ovarian stimulation (COS) for women undergoing Assisted Reproductive Technologies (ART).[1] Developed by Ferring Pharmaceuticals, it is a recombinant human follicle-stimulating hormone (rFSH) distinguished by two pioneering characteristics: its production in a human-derived cell line and its application of a prospective, individualized dosing algorithm based on patient-specific biomarkers.[3] These innovations collectively address the long-standing clinical challenge of balancing the efficacy of ovarian stimulation with the critical need for patient safety.

The core clinical proposition of Follitropin delta is its ability to achieve reproductive outcomes that are non-inferior, and in certain populations statistically superior, to those of conventional follitropins (follitropin alfa and follitropin beta), while concurrently offering a markedly improved safety profile.[3] This is primarily characterized by a clinically and statistically significant reduction in the incidence of Ovarian Hyperstimulation Syndrome (OHSS), the most serious iatrogenic complication of COS.[5]

The mechanism behind this innovation is rooted in its unique biochemical properties. Follitropin delta is produced in the PER.C6® human cell line, resulting in a distinct glycosylation pattern that more closely mimics endogenous human FSH.[3] This structural difference confers a unique pharmacokinetic and pharmacodynamic profile, including reduced clearance and higher in vivo potency compared to rFSH products derived from Chinese hamster ovary (CHO) cells.[8] This heightened potency necessitates a departure from traditional dosing in International Units (IU), leading to the development of a validated, mass-based (microgram) dosing algorithm. This algorithm prospectively calculates the optimal daily dose for each patient based on her serum Anti-Müllerian Hormone (AMH) level and body weight, representing a paradigm shift towards precision medicine in fertility treatment.[4]

A robust body of evidence from a comprehensive global clinical trial program, including the pivotal Phase 3 trials ESTHER-1, GRAPE, and STORK, substantiates the drug's clinical value. These trials have consistently demonstrated across diverse patient populations—including European, North American, South American, Asian, and Japanese women—that the individualized Follitropin delta regimen achieves its therapeutic goals effectively.[3] The data confirm non-inferiority in oocyte yield and pregnancy rates while consistently showing a superior safety profile, particularly in mitigating the risk of excessive ovarian response. Notably, the GRAPE trial in a pan-Asian population demonstrated a statistically significant higher live birth rate with Follitropin delta compared to conventional follitropin alfa.[6]

In conclusion, Follitropin delta is not merely an alternative gonadotropin but an integrated therapeutic system that combines a novel biologic with a validated, biomarker-driven dosing strategy. It signifies a move away from reactive, one-size-fits-all dosing towards a more predictable, patient-centric approach. By aiming for an optimal, rather than maximal, ovarian response, it reframes the goals of COS to prioritize a harmonized balance between achieving high efficacy and ensuring patient safety, thereby establishing a new standard in the management of ovarian stimulation for ART.

II. Biochemical Profile and Advanced Pharmacology

The distinct clinical profile of Follitropin delta is a direct consequence of its unique molecular architecture and resulting pharmacological behavior. Its development represents a deliberate effort to engineer a recombinant gonadotropin that more closely resembles the native human hormone, leading to significant differences in its interaction with physiological systems compared to previously developed rFSH preparations.

A. A Novel Recombinant Gonadotropin: The Human Cell Line Origin

The foundational innovation of Follitropin delta lies in its manufacturing process. It is a recombinant human FSH produced via recombinant DNA technology within a proprietary human cell line, PER.C6®, which is derived from fetal retinal cells.[3] This marks a fundamental departure from the established rFSH products, follitropin alfa and follitropin beta, which are produced in non-human, Chinese hamster ovary (CHO) cell lines.[3] While the primary amino acid sequences of the α and β subunits of Follitropin delta are identical to those of endogenous human FSH and other recombinant follitropins, the choice of the host cell line has profound implications for the molecule's post-translational modifications, particularly its glycosylation.[8]

Glycosylation, the enzymatic process of attaching carbohydrate chains (glycans) to proteins, is critical for the biological activity, stability, and pharmacokinetic profile of glycoprotein hormones like FSH. The cellular machinery responsible for this process differs between species, meaning that proteins expressed in different cell lines will exhibit distinct glycan structures. Follitropin delta's production in a human cell line results in a glycosylation profile that more closely mirrors that of native FSH circulating in humans.[3] A key biochemical differentiator is the nature of the sialic acid linkages. Sialic acid is a terminal sugar on the glycan chains that significantly influences the hormone's circulatory half-life. Follitropin delta possesses both α2,3- and α2,6-linked sialic acid residues, a characteristic of human-derived glycoproteins.[8] In contrast, follitropins produced in CHO cells contain exclusively α2,3-linked sialic acid.[12] This difference, along with other variations in glycan structure such as a higher degree of antennarity and fucosylation, contributes to a higher overall sialic acid content and a unique molecular signature that dictates its pharmacological behavior.[9]

B. Comparative Pharmacokinetics and Pharmacodynamics

The "human-like" glycosylation of Follitropin delta is not merely a structural curiosity; it is the direct cause of its distinct pharmacokinetic and pharmacodynamic profile, which sets it apart from CHO-derived rFSH. The primary mechanism for this difference lies in its reduced rate of clearance from the circulation. The clearance of glycoprotein hormones is largely mediated by specific receptors in the liver, including the asialoglycoprotein receptor (ASGPR), which recognizes and removes glycoproteins with exposed terminal galactose residues (i.e., those that have lost their terminal sialic acid).[9] The high degree of sialylation on Follitropin delta effectively shields these underlying sugar residues, reducing its affinity for and clearance by the ASGPR.[9]

This biochemical property translates into clinically significant pharmacokinetic advantages. Comparative studies have demonstrated that the apparent clearance of Follitropin delta is approximately 1.6-fold lower than that of follitropin alfa.[8] This slower clearance results in a longer terminal half-life—ranging from approximately 50 to 60 hours after a single subcutaneous administration—and a substantially higher systemic exposure for a given dose.[9] When equal doses based on International Units (IU) of Follitropin delta and follitropin alfa were administered daily for seven days in clinical studies, the resulting area under the curve (AUC), a measure of total drug exposure, was 1.7-fold higher for Follitropin delta, and the maximum serum concentration (Cmax) was 1.6-fold higher.[8]

This altered pharmacokinetic profile has a direct impact on the drug's in vivo pharmacodynamic effect, or potency. While the in vitro potency of follitropins at the FSH receptor may be similar, the sustained higher concentrations of Follitropin delta in the circulation lead to a more pronounced biological response.[9] It has been estimated that Follitropin delta is approximately 60% more potent than other rFSH preparations in vivo with respect to follicle recruitment.[3] This enhanced potency invalidates the traditional bioassay-based IU measurement for clinical dosing, as the IU does not accurately reflect the drug's behavior in humans. Consequently, Follitropin delta is dosed by mass in micrograms (mcg), and its dosing regimen is specific to the drug; the microgram dose cannot be directly converted to or applied to any other gonadotropin.[9] This causal chain—from the human cell line origin to the unique glycosylation, to the reduced clearance and enhanced potency, and finally to the necessity of a novel, mass-based dosing system—is fundamental to understanding the drug's development and clinical application.

Feature	Follitropin Delta (Rekovelle®)	Follitropin Alfa / Beta (e.g., Gonal-f®, Follistim®)
Host Cell Line	Human (PER.C6®) 3	Chinese Hamster Ovary (CHO) 3
Sialic Acid Linkage	α2,3- and α2,6-linked 8	Exclusively α2,3-linked 12
Apparent Clearance	Lower 8	Higher 8
Terminal Half-Life (single SC dose)	~50–60 hours 9	Shorter
Relative AUC (vs. Alfa)	~1.7-fold higher 8	1.0 (Reference)
Relative Cmax (vs. Alfa)	~1.6-fold higher 8	1.0 (Reference)
Dosing Unit	Micrograms (mcg) 9	International Units (IU) 9

C. Mechanism of Action

At the cellular level, the mechanism of action of Follitropin delta is identical to that of endogenous FSH and other exogenous follitropin preparations.[13] The hormone exerts its biological effects by binding specifically to the FSH receptor, a G-protein coupled receptor located on the plasma membrane of granulosa cells in the ovary.[13]

This ligand-receptor binding initiates a cascade of intracellular signaling events. It activates the enzyme adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).[16] The accumulation of intracellular cAMP, acting as a second messenger, subsequently activates protein kinase A (PKA). PKA then phosphorylates a variety of downstream target proteins, including transcription factors, which modulate the expression of genes essential for follicular growth and steroidogenesis.[16]

One of the most critical downstream effects is the upregulation of the enzyme aromatase (CYP19A1) within the granulosa cells.[16] Aromatase is responsible for the conversion of androgens (produced by theca cells under the influence of luteinizing hormone) into estrogens, primarily estradiol. The rising levels of estradiol are crucial for the proliferation of granulosa cells, the increase in follicular fluid, and the overall maturation of the ovarian follicle into a Graafian follicle capable of ovulation.[13] In the context of ART, the administration of exogenous Follitropin delta provides a supraphysiological FSH signal that overrides the normal feedback mechanisms of a single dominant follicle selection. This allows for the simultaneous growth and development of multiple mature follicles, which is the primary therapeutic objective of COS, thereby increasing the number of oocytes available for retrieval and subsequent fertilization.[3]

III. Clinical Application and The Individualized Dosing Strategy

The clinical application of Follitropin delta is defined by its specific indication for ART and is inextricably linked to its innovative, biomarker-driven dosing algorithm. This strategy represents a significant departure from traditional gonadotropin dosing, shifting the paradigm from a reactive, trial-and-error approach to a proactive, predictive model of care.

A. Approved Therapeutic Indication

Follitropin delta has a focused and specific therapeutic indication. It is approved for controlled ovarian stimulation (COS) for the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle.[14] The treatment must be initiated and managed by a physician with extensive experience in the diagnosis and treatment of fertility problems, ensuring that patients receive appropriate monitoring and care throughout the stimulation process.[1]

B. The Follitropin Delta Individualized Dosing Algorithm

The dosing algorithm for Follitropin delta is its most defining clinical feature and was developed as a direct necessity of its unique PK/PD profile. The conventional approach to COS often involves starting with a standard dose of gonadotropin (e.g., 150 IU) and then reactively adjusting it after several days based on the observed ovarian response via ultrasound and hormonal monitoring.[11] This method can be imprecise, with a risk of initial over- or under-stimulation before adjustments can be made.

In contrast, the Follitropin delta algorithm employs a proactive philosophy. It uses pre-treatment biomarkers to prospectively calculate a patient-specific daily dose that is intended to remain fixed throughout the entire stimulation period.[20] The primary objective of this algorithm is to guide the ovarian response into a predefined optimal window—typically defined as the retrieval of 8 to 14 oocytes—which has been associated with a high probability of achieving a live birth while minimizing the risks of both poor response (leading to cycle cancellation) and excessive response (which increases the risk of OHSS).[3]

The algorithm is based on two core, patient-specific parameters:

1. Serum Anti-Müllerian Hormone (AMH) Concentration: AMH is a well-established biomarker of ovarian reserve and is a strong predictor of how a patient's ovaries will respond to gonadotropin stimulation.[10] For the algorithm to be applied correctly, the AMH level must have been measured within the previous 12 months using a specifically validated and approved diagnostic assay, such as the Roche Elecsys® AMH Plus or the Beckman Coulter Access AMH Advanced immunoassay.[21]
2. Body Weight: There is an inverse relationship between a patient's body weight and the resulting serum concentrations of FSH following subcutaneous administration.[9] Incorporating body weight into the calculation helps to normalize drug exposure across patients of different sizes.[21]

The dosing regimen for the first treatment cycle is stratified based on the patient's AMH level:

AMH Concentration (pmol/L)	Daily Dose (fixed throughout stimulation)
<15	12 micrograms (fixed)
15–16	0.19 micrograms/kg
17–18	0.18 micrograms/kg
19–20	0.17 micrograms/kg
21–22	0.15 micrograms/kg
23–24	0.14 micrograms/kg
25–27	0.13 micrograms/kg
28–32	0.12 micrograms/kg
33–39	0.11 micrograms/kg
≥40	0.10 micrograms/kg

Note: AMH in ng/mL should be converted to pmol/L by multiplying by 7.14. The maximum daily dose for the first treatment cycle is 12 micrograms. The calculated dose is rounded to the nearest 0.33 micrograms to match the injection pen's scale. [17]

For subsequent treatment cycles, the dose may be adjusted based on the response observed in the preceding cycle, with a maximum allowable daily dose of 24 micrograms.[14] If the patient had a hyper-response or developed OHSS, the dose is decreased by 20-33%.[15] If the response was inadequate (hypo-response), the dose is increased by 25-50%.[21] If the response was adequate, the same daily dose is maintained.[24]

While this algorithm is a significant advance, emerging data suggest areas for potential refinement. For instance, the fixed 12 microgram ceiling for all patients with AMH <15 pmol/L may not be sufficient for the specific subgroup of women who have both low AMH and high body weight.[26] One study noted that for every 10 kg increase in body weight in this group, the oocyte yield decreased by approximately 0.7, indicating that these patients might benefit from a slightly higher dose than the current algorithm allows.[26] Furthermore, the drug's perceived value has led to off-label use in indications like controlled ovarian hyperstimulation for intrauterine insemination (COH-IUI), where the goal is far fewer follicles.[27] Early data from this off-label use show that applying the IVF algorithm directly leads to high rates of overstimulation (45.4%), highlighting the critical need for the development and validation of new, indication-specific algorithms with much lower starting doses (e.g., 2.0-4.0 mcg/day) to ensure safety in these different clinical contexts.[27]

C. Administration and Clinical Monitoring

Follitropin delta is formulated as a solution for injection in a pre-filled, multi-dose cartridge designed for use with the reusable Rekovelle® injection pen.[8] Administration is via subcutaneous injection, and while the first dose must be given under direct medical supervision, patients or their partners can be trained to perform subsequent injections at home.[1]

Treatment is typically initiated on day 2 or 3 of the menstrual cycle and is continued daily until adequate follicular development is achieved.[17] This endpoint is defined as the presence of at least three follicles measuring 17 mm or more in diameter, as assessed by transvaginal ultrasound.[17] The average duration of stimulation to reach this point is nine days, with a typical range of 5 to 20 days.[17]

Throughout the stimulation phase, diligent monitoring is essential for both safety and efficacy. This involves regular transvaginal ultrasound scans to assess follicular growth and endometrial thickness, often complemented by serial measurements of serum estradiol levels.[17] This monitoring allows the clinician to track the response, confirm that development is proceeding as expected, and, most importantly, identify patients who may be developing an excessive response. In such cases, where 25 or more follicles of ≥12 mm are observed, treatment with Follitropin delta should be discontinued, and the final maturation trigger (hCG) must be withheld to prevent the onset of clinically significant OHSS.[15]

IV. Analysis of Clinical Efficacy and Safety: Pivotal Phase 3 Trials

The clinical value of Follitropin delta is supported by a comprehensive program of large-scale, randomized, controlled Phase 3 trials conducted across diverse global populations. These studies—ESTHER-1, GRAPE, and STORK—were designed to compare the individualized Follitropin delta regimen against the established standards of care, follitropin alfa and follitropin beta, providing robust evidence for its efficacy and safety profile.

A. The ESTHER-1 Trial: The Foundation of Non-Inferiority and Improved Safety

The ESTHER-1 trial (Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World) served as the cornerstone of the initial regulatory submissions for Follitropin delta.[29] This large, randomized, assessor-blind, non-inferiority trial enrolled 1,329 women between the ages of 18 and 40 across 11 countries, making its findings broadly generalizable.[11] The trial compared the individualized, fixed-dose Follitropin delta regimen against a conventional, adjustable-dose regimen of follitropin alfa, which started at 150 IU/day for the first five days.[11]

The trial successfully met its primary co-endpoints, establishing non-inferiority for both ongoing pregnancy rate and ongoing implantation rate. The ongoing pregnancy rate was 30.7% in the Follitropin delta group versus 31.6% in the follitropin alfa group, a statistically non-inferior result.[11] Similarly, the live birth rate was comparable between the two arms, at 29.8% for Follitropin delta and 30.7% for follitropin alfa.[11]

While the mean number of oocytes retrieved was similar between the groups (10.0 for Follitropin delta vs. 10.4 for follitropin alfa), a deeper analysis of the ovarian response revealed a key advantage of the individualized approach. The Follitropin delta regimen was more effective at guiding patients into the desired therapeutic window. A significantly higher proportion of women treated with Follitropin delta achieved the target response of 8–14 oocytes (43.3% vs. 38.4%).[3] This demonstrates a shift away from simply maximizing oocyte yield towards achieving an optimal yield. The strategy aims for a cohort of oocytes that is sufficient for a high chance of success without pushing the ovaries to a state of excessive stimulation, which is the primary driver of OHSS.

This focus on an optimal, rather than maximal, response translated directly into an improved safety profile. The incidence of excessive ovarian response (defined as ≥15 oocytes in patients with high AMH) was lower in the Follitropin delta arm (27.9% vs. 35.1%).[11] Critically, this led to a significant reduction in the need for clinical interventions to prevent OHSS, with such measures being required in only 2.3% of Follitropin delta cycles compared to 4.5% of follitropin alfa cycles.[11]

Outcome	Follitropin Delta	Follitropin Alfa	Result (Difference, 95% CI)
Ongoing Pregnancy Rate	30.7%	31.6%	-0.9% (-5.9% to 4.1%)
Live Birth Rate	29.8%	30.7%	-0.9% (-5.8% to 4.0%)
Mean Oocytes Retrieved	10.0 ± 5.6	10.4 ± 6.5	Similar
Target Response (8-14 oocytes)	43.3%	38.4%	Follitropin delta favored
OHSS Preventive Interventions	2.3%	4.5%	Follitropin delta favored

Data from the ESTHER-1 Trial [11]

B. The GRAPE Trial: Demonstrating Superior Live Birth Rates in an Asian Population

The GRAPE trial was a randomized, controlled, assessor-blind study conducted in a pan-Asian population of 1,009 women, designed to validate the efficacy and safety of the individualized Follitropin delta regimen in this specific demographic.[6] The comparator was again a conventional follitropin alfa regimen with a 150 IU starting dose.[6]

The GRAPE trial not only confirmed the findings of ESTHER-1 but also produced a striking result regarding the primary clinical endpoint. While non-inferiority was established for the ongoing pregnancy rate (31.3% for Follitropin delta vs. 25.7% for follitropin alfa), the trial demonstrated a statistically significant higher live birth rate in the Follitropin delta arm: 31.3% versus 24.7% (p=0.023).[6] This finding is of profound clinical importance, as it elevates Follitropin delta from being merely a safer alternative to a potentially more effective one in this patient population. This suggests that the precise control over follicular dynamics afforded by the individualized algorithm may, in certain ethnic groups, translate into improved oocyte or endometrial quality, leading to better implantation and successful term pregnancies.

Consistent with other trials, the overall mean number of oocytes retrieved was lower with Follitropin delta (10.0 vs. 12.4), yet the algorithm effectively modulated the response according to ovarian reserve, retrieving more oocytes from predicted low responders and fewer from predicted high responders compared to the conventional approach.[6] This targeted response again led to a superior safety profile, with the incidence of early OHSS and/or the need for preventive interventions being significantly reduced by half in the Follitropin delta group (5.0% vs. 9.6%; p=0.004).[6]

The combination of higher efficacy and improved safety, achieved with a lower total gonadotropin dose, also has significant pharmacoeconomic implications. An economic analysis based on the GRAPE trial data concluded that Follitropin delta was a "dominant" treatment strategy in this context, meaning it was both more effective (higher live birth rate) and less costly than follitropin alfa.[30] This provides a compelling argument for its adoption not only from a clinical perspective but also from a health system resource allocation standpoint.

Outcome	Follitropin Delta	Follitropin Alfa	Result (Difference, 95% CI, p-value)
Ongoing Pregnancy Rate	31.3%	25.7%	5.4% (-0.2% to 11.0%)
Live Birth Rate	31.3%	24.7%	6.6% (0.9% to 11.9%); p=0.023
Mean Oocytes Retrieved	10.0 ± 6.1	12.4 ± 7.3	p < 0.001
Early OHSS / Preventive Interventions	5.0%	9.6%	p=0.004

Data from the GRAPE Trial [6]

C. The STORK Trial: Non-Inferiority and Safety vs. Follitropin Beta in Japan

The STORK trial was conducted specifically in a population of 347 Japanese women undergoing their first ART cycle, comparing individualized Follitropin delta to a conventional dosing regimen of follitropin beta (150 IU starting dose).[3] The primary endpoint for this study was the number of oocytes retrieved.[7]

The trial successfully met its primary objective, establishing the non-inferiority of Follitropin delta with a mean of 9.3 oocytes retrieved compared to 10.5 for follitropin beta.[7] Although the trial was not powered to detect a difference in pregnancy outcomes, the live birth rate was numerically higher in the Follitropin delta arm (23.5% vs. 18.6%).[7]

The most significant finding of the STORK trial was the dramatic improvement in safety. The individualized Follitropin delta regimen reduced the incidence of OHSS of any grade by approximately half, from 19.8% with conventional follitropin beta to 11.2% (p=0.021).[7] The reduction was even more pronounced for clinically significant moderate-to-severe OHSS, with the incidence falling from 14.1% to 7.1% (p=0.027).[7] These results provided strong evidence that the individualized approach offers a favorable benefit-risk profile, achieving a comparable oocyte yield with a statistically significant and clinically meaningful reduction in OHSS risk.

Outcome	Follitropin Delta	Follitropin Beta	Result (p-value)
Mean Oocytes Retrieved	9.3	10.5	Non-inferior
Live Birth Rate	23.5%	18.6%	Not statistically powered
Incidence of any OHSS	11.2%	19.8%	p=0.021
Incidence of moderate/severe OHSS	7.1%	14.1%	p=0.027

Data from the STORK Trial [7]

V. Comprehensive Safety and Prescribing Information

The clinical use of Follitropin delta, like all potent gonadotropins, requires a thorough understanding of its safety profile, contraindications, and potential adverse effects. The individualized dosing algorithm is designed to mitigate many of these risks, but careful patient selection and monitoring remain paramount.

A. Adverse Drug Reactions

The safety profile of Follitropin delta has been well-characterized through its extensive clinical trial program. The most frequently reported adverse drug reactions are generally mild to moderate and consistent with the known effects of ovarian stimulation.[13]

System Organ Class	Frequency	Adverse Reaction
Nervous system disorders	Common (≥1/100 to <1/10)	Headache
	Uncommon (≥1/1,000 to <1/100)	Mood swings, Dizziness, Somnolence (drowsiness)
Gastrointestinal disorders	Common (≥1/100 to <1/10)	Nausea
	Uncommon (≥1/1,000 to <1/100)	Diarrhoea, Vomiting, Constipation, Abdominal discomfort
Reproductive system and breast disorders	Common (≥1/100 to <1/10)	Ovarian Hyperstimulation Syndrome (OHSS), Pelvic pain, Pelvic discomfort, Adnexa uteri (ovarian/tubal) pain
	Uncommon (≥1/1,000 to <1/100)	Vaginal haemorrhage, Breast complaints (pain, tenderness)
General disorders	Common (≥1/100 to <1/10)	Fatigue

Data compiled from [13]

In post-marketing surveillance, rare but serious events such as ovarian torsion have been reported, typically occurring as a complication of severe ovarian enlargement associated with OHSS.[13] As with any injectable protein, there is also a risk of hypersensitivity or allergic reactions, which may manifest as rash, itching, hives, or more severe systemic reactions like wheezing, shortness of breath, or angioedema.[39]

B. Contraindications

The use of Follitropin delta is strictly contraindicated in several clinical situations where its use would be either unsafe or futile. These absolute contraindications include [15]:

• Known hypersensitivity to follitropin delta or any of the listed excipients.
• Tumours of the hypothalamus or pituitary gland.
• Ovarian, uterine, or mammary carcinoma.
• Active, undiagnosed gynaecological haemorrhages.
• Ovarian enlargement or the presence of an ovarian cyst that is not attributable to Polycystic Ovarian Syndrome (PCOS).
• Current pregnancy or lactation.

Additionally, treatment should not be initiated in circumstances where a favorable outcome is highly unlikely, such as [15]:

• Primary ovarian failure, as indicated by high baseline FSH levels.
• Congenital malformations of the sexual organs that are incompatible with pregnancy.
• Fibroid tumours of the uterus that would prevent implantation or normal gestation.

C. Warnings and Precautions for Use

The most consistent and statistically significant advantage demonstrated by Follitropin delta in its clinical development program is its improved safety profile, particularly the reduction in OHSS. This underscores that OHSS remains the primary safety concern with any form of COS, and its prevention is a central goal of the individualized dosing strategy.

• Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a systemic and potentially severe complication arising from an exaggerated ovarian response to gonadotropin stimulation. It is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space due to increased vascular permeability.[17] Mild symptoms include abdominal pain, pelvic discomfort, nausea, and weight gain. Severe cases can progress to involve ascites, pleural effusions, dyspnoea, oliguria, haemoconcentration, and an increased risk of thromboembolic events.[17] The risk of OHSS is minimized by strict adherence to the Follitropin delta dosing algorithm and careful patient monitoring.[17] If signs of an excessive ovarian response (e.g., ≥25 follicles ≥12 mm) are detected, the final maturation trigger with hCG must be withheld, as hCG administration is the key event that precipitates clinically significant OHSS.[17]
• Thromboembolic Events: Gonadotropin therapy may increase the risk of venous or arterial thromboembolic events, particularly in women with pre-existing risk factors such as severe obesity (BMI >30 kg/m2), a personal or family history of thrombosis, or known thrombophilia.[17] It is important to note that pregnancy itself, as well as OHSS, are independent risk factors for thromboembolism.[41]
• Ovarian Torsion: Twisting of an enlarged ovary can occur, compromising its blood supply and potentially leading to necrosis. This is a rare complication, most often seen in the context of significant ovarian enlargement from OHSS.[36]
• Multiple Pregnancy: The risk of multiple gestation is inherent to all ART procedures and is primarily related to the number of embryos transferred.[1] Patients should be counseled on the increased maternal and fetal risks associated with multiple pregnancies.
• Other Pregnancy-Related Risks: As with other ART treatments, there may be a higher risk of ectopic pregnancy, particularly in women with a history of tubal disease, and a higher rate of spontaneous abortion (miscarriage) compared to natural conception.[1]
• Pre-treatment Assessment: Prior to initiating therapy, it is imperative to conduct a thorough evaluation of the couple's infertility and to screen for any contraindications to pregnancy. Endocrine disorders such as hypothyroidism or hyperprolactinemia should be appropriately diagnosed and treated before commencing COS.[15]

D. Drug Interaction Profile

The potential for drug-drug interactions with Follitropin delta is considered to be very low. To date, no dedicated drug-drug interaction studies have been conducted.[13]

From a pharmacological standpoint, clinically significant interactions are not anticipated. As a large glycoprotein, Follitropin delta is unlikely to bind to plasma proteins or to be metabolized by or interact with the cytochrome P450 (CYP450) enzyme system, which is the primary pathway for the metabolism of many small-molecule drugs.[13] Furthermore, throughout the extensive clinical trial program involving thousands of patients, no clinically relevant drug interactions were observed or reported.[13]

Despite the low theoretical risk, standard clinical prudence dictates that patients should be advised to inform their physician of all medications they are currently taking, including prescription drugs, over-the-counter medicines, vitamins, and herbal supplements, before starting treatment with Follitropin delta.[1]

VI. Regulatory Landscape and Global Approvals

The regulatory pathway for Follitropin delta has seen successful marketing authorisations in major global regions, including Europe, Canada, and Australia, based on a robust data package from its Phase 3 clinical trial program. However, its status in the United States presents a more complex picture, suggesting a distinct and ongoing regulatory process.

A. European Medicines Agency (EMA)

The regulatory process in Europe was initiated on October 30, 2015, when the EMA accepted the Marketing Authorisation Application for Follitropin delta for review.[29] The submission was primarily supported by the comprehensive efficacy and safety data from the Phase 3 ESTHER-1 and ESTHER-2 trials.[29] Following a positive assessment, the European Commission granted formal marketing authorisation on

December 12, 2016.[45] The approval was for its use in controlled ovarian stimulation for women undergoing ART.[45] Subsequently, in October 2023, the product's label was updated to include data on its use in conjunction with a gonadotropin-releasing hormone (GnRH) agonist protocol, based on the results of the BEYOND trial.[48]

B. Health Canada

In Canada, the New Drug Submission for Rekovelle was filed on December 17, 2015.[49] The review process included the issuance of a Notice of Deficiency (NOD) on November 21, 2016. Health Canada's Biologics and Genetic Therapies Directorate raised concerns regarding the appropriateness of the selected co-primary endpoints in the pivotal trials to support the proposed indication.[49] The sponsor, Ferring Inc., successfully addressed these deficiencies in its response, and after a second review, Health Canada issued a Notice of Compliance, granting approval on

March 22, 2018.[49]

C. Therapeutic Goods Administration (TGA), Australia

In Australia, Follitropin delta received a positive decision from the TGA on March 24, 2017. It was officially entered onto the Australian Register of Therapeutic Goods (ARTG) one week later, on March 31, 2017, making it available for prescription for its approved ART indication.[14]

D. Status in the United States (U.S. Food and Drug Administration - FDA)

The regulatory status of Follitropin delta in the United States is notably different from other major jurisdictions. The provided documentation contains no evidence of an official marketing approval by the U.S. FDA.[49] This conspicuous absence, several years after its approval in Europe, suggests a distinct and more rigorous regulatory pathway in the U.S.

Evidence strongly indicates that Ferring Pharmaceuticals has been actively pursuing U.S. approval through a dedicated clinical development program. Two large-scale, randomized, double-blind, placebo-controlled Phase 3 trials, known as RITA-1 (NCT03740737) and RITA-2 (NCT03738618), were conducted exclusively at reproductive medicine clinics within the United States.[52] Enrollment for these trials began in October 2018, nearly two years after the EMA approval, which implies that the FDA likely required additional data generated specifically within the U.S. patient population rather than accepting the global data package from the ESTHER trials as sufficient for a Biologics License Application (BLA).

A critical difference in the design of the RITA trials was the dosing strategy employed. Instead of the AMH- and body weight-based fixed-dose algorithm used in the global trials, the U.S. trials investigated a fixed starting dose based on maternal age (12 µg/day for patients <35 years and 15 µg/day for patients ≥35 years), which notably allowed for subsequent dose adjustments during the stimulation cycle.[52] This divergence may reflect an FDA requirement to test a dosing paradigm more aligned with conventional U.S. clinical practice or to generate data on an alternative to the biomarker-driven algorithm. The results from the RITA trials demonstrated high efficacy and an acceptable safety profile in the U.S. population, with cumulative live birth rates of 62.5% in women <35 years and 42.4% in women ≥35 years.[52] These data will undoubtedly form the basis of any future regulatory submission to the FDA, and the final outcome of that process remains a key development in the global story of Follitropin delta.

VII. Concluding Analysis and Future Perspectives

A. Summary of Follitropin Delta's Clinical Profile

Follitropin delta (Rekovelle®) has established itself as a novel and valuable agent in the therapeutic armamentarium for assisted reproductive technologies. Its foundation lies in a unique biochemical design, originating from a human cell line, which confers a distinct pharmacokinetic profile characterized by reduced clearance and enhanced in vivo potency. This necessitated the development of an innovative, biomarker-driven dosing algorithm that prospectively individualizes treatment based on a woman's ovarian reserve (AMH) and body weight. The collective evidence from a rigorous global clinical trial program consistently demonstrates that this integrated therapeutic system achieves robust efficacy, with pregnancy and live birth rates that are non-inferior, and in the pan-Asian population superior, to conventional follitropins. This efficacy is coupled with a superior and clinically meaningful safety profile, most notably a significant reduction in the risk of Ovarian Hyperstimulation Syndrome.

B. A Paradigm Shift in Controlled Ovarian Stimulation

The introduction of Follitropin delta marks a significant evolution in the clinical philosophy of controlled ovarian stimulation. It represents a validated and successful transition from a reactive, population-based dosing model to a proactive, personalized medicine approach.[3] For decades, the practice of COS has involved initiating a standard dose and making subsequent adjustments based on observed response, a method that carries an inherent risk of initial over- or under-stimulation. The Follitropin delta algorithm fundamentally alters this paradigm by using pre-treatment biomarkers to predict and target an optimal response from the outset.[3]

This strategy reframes the goal of stimulation. Instead of aiming for the maximal number of oocytes, it prioritizes achieving a predictable and optimal yield (8–14 oocytes), a range associated with a high likelihood of success and a lower risk of complications.[3] By doing so, it enhances patient safety without compromising the ultimate clinical objective of a live birth. This shift towards a more controlled, predictable, and safer stimulation cycle represents a substantial practical advancement in the field of reproductive medicine.

C. Future Perspectives and Unanswered Questions

Despite its established profile, several areas for future research and development remain for Follitropin delta.

• Refining the Algorithm: While highly effective for a broad range of patients, emerging evidence suggests the current algorithm may have limitations at the extremes of patient characteristics. Specifically, further investigation is warranted to determine if the 12-microgram daily dose ceiling for the first cycle is truly optimal for women with the combined challenge of low AMH and high body weight, or if a modest dose increase in this specific subgroup could improve oocyte yield without compromising safety.[26]
• Expansion to New Indications: The off-label use of Follitropin delta in IUI cycles highlights a clinical need and an opportunity.[27] The development and validation of a specific, low-dose algorithm for IUI could provide a safer, more predictable option for this common fertility treatment, but requires dedicated clinical trials to establish appropriate dosing and confirm safety.
• The U.S. Market: The regulatory status of Follitropin delta in the United States remains the most significant unanswered question. The completion of the U.S.-specific RITA trials provides a substantial data package for a potential FDA submission.[52] The final decision by the FDA, and critically, the specific dosing regimen that may be approved—whether it aligns with the global AMH-based algorithm or the age-based, adjustable-dose model studied in the RITA trials—will be a pivotal event that will shape its adoption and clinical positioning in the world's largest ART market.
• Long-Term and Cumulative Outcomes: The evidence for Follitropin delta's efficacy in fresh transfer cycles is robust. As more real-world data accumulates, further analysis of cumulative live birth rates—encompassing all fresh and frozen embryo transfers resulting from a single ovarian stimulation cycle—will continue to build the long-term evidence base and provide a more complete picture of the effectiveness of this personalized treatment strategy.[3]

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