A Comprehensive Monograph on Mecasermin (rhIGF-1): Pharmacology, Clinical Utility, and Safety Profile

Introduction and Drug Profile

Overview of Mecasermin

Mecasermin is a highly purified, biosynthetic form of human insulin-like growth factor-1 (IGF-1), produced through recombinant DNA technology.[1] It is classified pharmacologically as a somatotropin agonist and belongs to the therapeutic class of insulin-like growth factors.[2] Marketed globally under the brand name Increlex, mecasermin has also been identified by other names in research and development contexts, including Myotrophin, FK-780, and Somatomedin-1.[1]

The primary and approved therapeutic application of mecasermin is as a replacement therapy for endogenous IGF-1. It is indicated for the long-term treatment of growth failure in pediatric patients with severe primary IGF-1 deficiency (SPIGFD).[1][ This specific and narrowly defined condition is characterized by an inability to produce sufficient IGF-1 despite normal or elevated levels of growth hormone (GH), rendering GH therapy ineffective. Mecasermin directly addresses this downstream defect, providing the essential mediator for statural growth.]

Physicochemical and Structural Properties

Mecasermin is a product of advanced biotechnology, specifically manufactured using genetically engineered Escherichia coli bacteria.[10] The manufacturing process is a multi-step procedure that begins with the production of rhIGF-1 in an inactive, unfolded form within the periplasmic space of the bacterial cells. This crude protein is then isolated and subjected to a controlled refolding process to achieve its precise, biologically active three-dimensional conformation. The final stage involves a rigorous purification cascade, employing column chromatography and ultrafiltration, to remove process-related impurities (e.g., host cell proteins) and product-related variants, ensuring the high purity and safety of the final drug substance.[10]

The choice of an E. coli expression system has direct implications for the final molecular structure of mecasermin. Unlike mammalian cell culture systems, bacterial systems cannot perform complex post-translational modifications such as glycosylation. Consequently, mecasermin is a non-glycosylated polypeptide.[10][ While this simplifies the manufacturing process and can enhance production efficiency, it also distinguishes the recombinant protein from some of its endogenous counterparts and other therapeutic proteins. The absence of glycosylation can influence a protein's pharmacokinetic profile, including its stability and half-life, and potentially its immunogenicity. This underscores the critical importance of the refolding and purification steps to ensure that the final product is structurally identical to native human IGF-1 and free from contaminants that could provoke an immune response.]

Structurally, mecasermin is a single-chain polypeptide composed of 70 amino acids. Its conformation is stabilized by three intramolecular disulfide bridges, which are essential for its biological activity. The specific linkages are between cysteine residues at positions 6 and 48, and 18 and 61.[6] Critically, the primary amino acid sequence of mecasermin is identical to that of native, endogenously produced human IGF-1, ensuring that it can bind to and activate the IGF-1 receptor with the same affinity and specificity as the natural hormone.[6]

From a chemical standpoint, mecasermin is defined by the molecular formula C331​H512​N94​O101​S7​. Its molecular weight has been confirmed to be approximately 7648.71 g·mol⁻¹, which is in close agreement with the theoretically calculated mass of 7649.6 daltons for the 70-amino acid polypeptide.[1]

Identifier	Value	Source
International Nonproprietary Name	Mecasermin	10
Brand Name	Increlex	1
Drug Type	Biotech
DrugBank Accession Number	DB01277	1
CAS Registry Number	68562-41-4	1
ATC Code	H01AC03	1
FDA UNII	7GR9I2683O	1
Molecular Formula	C331​H512​N94​O101​S7​	1
Molar Mass	7648.71 g·mol⁻¹	1

Clinical Pharmacology

Mechanism of Action

The mechanism of action of mecasermin is fundamentally rooted in its function as a direct replacement for endogenous insulin-like growth factor-1, thereby circumventing defects in the growth hormone (GH)-IGF-1 axis. In healthy individuals, GH secreted from the pituitary gland binds to GH receptors on hepatocytes (liver cells) and other tissues, stimulating the synthesis and secretion of IGF-1. IGF-1 then acts as the principal mediator of GH's anabolic and growth-promoting effects.[4]

However, in patients with severe primary IGF-1 deficiency, such as those with Laron syndrome, this pathway is disrupted. These individuals may have genetic mutations affecting the GH receptor or post-receptor signaling pathways. As a result, their tissues are insensitive to GH, leading to a failure to produce adequate amounts of IGF-1 despite having normal or even elevated circulating levels of GH.[4] Mecasermin therapy is designed to act downstream of this physiological blockade. By providing an exogenous source of IGF-1, it bypasses the non-functional GH receptor and directly restores the necessary signal for somatic growth.[4]

Once administered, mecasermin binds with high affinity to the Type I IGF-1 receptor (IGF-1R). This receptor is a member of the tyrosine kinase receptor superfamily and is ubiquitously expressed on the surface of virtually all cell types throughout the body.[4] The binding of mecasermin to the IGF-1R induces a conformational change in the receptor, leading to its dimerization and subsequent autophosphorylation on specific tyrosine residues within its intracellular domain. This activation event serves as a docking site for various intracellular substrate and adapter proteins, primarily the insulin-receptor substrates (IRS1/2) and Shc.[4]

[The phosphorylation of these substrates triggers the activation of two major downstream signaling cascades that are central to the biological effects of IGF-1:]

1. The Phosphoinositide 3-Kinase (PI3K)-AKT Pathway: This pathway is a critical regulator of cell growth, survival, and metabolism. Activated IRS proteins recruit and activate PI3K, which in turn generates the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3​). PIP3​ recruits the serine/threonine kinase AKT (also known as Protein Kinase B) to the cell membrane, where it is activated. Activated AKT then phosphorylates a multitude of downstream targets, leading to the promotion of glucose uptake, stimulation of protein synthesis (via the mTOR pathway), and potent inhibition of apoptosis (programmed cell death). This cascade is directly responsible for the anabolic and cell survival effects that drive tissue and organ growth.[4]
2. The Ras-Raf-MAPK (Mitogen-Activated Protein Kinase) Pathway: This pathway is primarily involved in mediating cell proliferation (mitogenesis) and differentiation. The recruitment of the Grb2/SOS adapter protein complex to the activated receptor or IRS proteins leads to the activation of the small G-protein Ras. Ras, in turn, initiates a kinase cascade involving Raf, MEK, and ERK (extracellular signal-regulated kinase). Activated ERK translocates to the nucleus, where it phosphorylates and activates transcription factors that regulate the expression of genes involved in cell cycle progression and division.[4]

The concerted action of these two pathways—the PI3K-AKT pathway driving cell growth and survival, and the MAPK pathway driving cell proliferation—results in the comprehensive promotion of somatic growth, affecting skeletal tissue, cells, and organs.[4]

Pharmacodynamics

[The pharmacodynamic effects of mecasermin are a direct reflection of the physiological roles of IGF-1 and are broadly categorized into growth-promoting and metabolic actions.]

The primary and intended pharmacodynamic effect is the stimulation of statural growth in children with IGF-1 deficiency. This is a complex process mediated by the activation of IGF-1R in various tissues. Specifically, mecasermin promotes mitogenesis (cell division) in multiple tissue types, stimulates the proliferation and differentiation of chondrocytes within the cartilaginous growth plates of long bones, and increases overall organ size. The cumulative result of these cellular actions is an increase in linear bone growth and an overall increase in body size and mass.[12]

In addition to its anabolic effects, mecasermin exerts potent metabolic effects, particularly on carbohydrate metabolism. These effects are described as "insulin-like" because the IGF-1R shares significant structural and functional homology with the insulin receptor, and their downstream signaling pathways (especially the PI3K-AKT pathway) overlap considerably. Mecasermin enhances insulin sensitivity, stimulates glucose uptake and utilization in peripheral tissues such as muscle and fat, and suppresses the production of glucose by the liver (hepatic gluconeogenesis).[4] The net effect of these actions is a significant reduction in blood glucose concentrations. This powerful glucose-lowering effect is not an off-target side effect but an intrinsic, on-target consequence of the drug's mechanism of action. The same PI3K-AKT signaling that drives therapeutic growth is also responsible for this potent metabolic effect. This duality is fundamental to understanding the clinical profile of mecasermin, as it directly explains why hypoglycemia is the most common and clinically significant adverse event associated with its use.[4]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

[The pharmacokinetic profile of mecasermin describes its movement into, through, and out of the body.]

Administration and Absorption: Mecasermin is formulated for subcutaneous injection, which is the sole route of administration.[1] Following subcutaneous injection in healthy adult subjects, the drug is completely absorbed, exhibiting a bioavailability of 100%.[14]

Distribution: Upon entering the systemic circulation, free IGF-1 is rapidly bound by a family of six specific insulin-like growth factor-binding proteins (IGFBPs). Over 80% of circulating IGF-1 becomes part of a large, non-covalent ternary complex, which consists of one molecule of IGF-1, one molecule of IGFBP-3 (the most abundant binding protein), and one molecule of a glycoprotein known as the acid-labile subunit (ALS).[12][ This 150 kDa complex acts as a physiological reservoir, protecting IGF-1 from rapid clearance and modulating its delivery to target tissues. In pediatric patients with severe primary IGFD, the volume of distribution (]

Vd​) for mecasermin has been determined to be approximately 0.257 L/kg.[12]

Metabolism and Elimination: As a polypeptide, mecasermin is expected to undergo metabolic degradation through proteolytic pathways, primarily in the liver and kidneys. It is broken down into smaller, inactive peptides and constituent amino acids, which are then re-utilized by the body or eliminated.[12] Specific studies detailing the effects of renal or hepatic impairment on the pharmacokinetics of mecasermin have not been conducted, and this remains an area with limited data.[15]

Half-Life and Clearance: In the target population of children with severe primary IGFD, the mean elimination half-life of mecasermin is approximately 5.8 hours.[1] An important pharmacokinetic characteristic of mecasermin is that its clearance from the body is inversely proportional to the circulating concentration of IGFBP-3.[12][ This relationship has profound clinical implications. Since patients with primary IGFD may have dysregulated levels of IGFBPs as part of their underlying pathology, the drug's half-life and systemic exposure can vary significantly between individuals, even at the same weight-based dose. A patient with lower IGFBP-3 levels will clear the drug more rapidly, potentially leading to lower overall exposure and a different peak-to-trough concentration profile. This inherent variability, dictated by the patient's own pathophysiology, underscores the necessity of careful, individualized dose titration and monitoring, as a standardized dosing approach may not yield predictable pharmacokinetic outcomes across all patients.]

A related but distinct medication, mecasermin rinfabate (brand name Iplex), was developed as a 1:1 molar complex of recombinant human IGF-1 (mecasermin) and recombinant human IGFBP-3.[1] The co-formulation with its primary binding protein was designed to mimic the natural ternary complex and prolong the drug's duration of action. This was successfully demonstrated in pharmacokinetic studies, where the half-life of mecasermin administered as mecasermin rinfabate was extended to 13.4 hours in patients with severe primary IGFD, more than double that of mecasermin alone.[1]

Parameter	Mecasermin (Increlex)	Mecasermin Rinfabate (Iplex)	Context / Patient Population
Route of Administration	Subcutaneous	Subcutaneous	Pediatric patients
Bioavailability	100%	Not specified	Healthy subjects (for mecasermin)
Time to Peak Concentration (Tmax​)	~2 hours	11.3 ± 6.2 hours	Severe Primary IGFD
Elimination Half-life (t1/2​)	~5.8 hours	13.4 ± 2.7 hours	Severe Primary IGFD
Volume of Distribution (Vd​/F)	0.257 ± 0.073 L/kg	Not specified	Severe Primary IGFD
Protein Binding	>80% (bound to IGFBPs)	Administered as a complex with IGFBP-3	In blood

Clinical Efficacy and Therapeutic Indications

Approved Indication: Severe Primary IGF-1 Deficiency (SPIGFD)

Mecasermin is approved for the long-term treatment of growth failure in a very specific pediatric population. The indication is for children aged 2 years and older who are diagnosed with severe primary insulin-like growth factor-1 deficiency (SPIGFD).[2][ The diagnosis of SPIGFD is rigorously defined by a triad of criteria:]

1. Severe short stature:[ Height standard deviation score (SDS) of -3.0 or less.]
2. Low IGF-1 levels:[ Basal serum IGF-1 concentrations below the 2.5th percentile for the child's age and gender.]
3. GH sufficiency: Normal or elevated secretion of growth hormone.[2]

This definition specifically identifies children whose growth failure is due to an inability to produce or respond to IGF-1, rather than a deficiency of GH itself. The indication also extends to a small subset of patients who have a GH gene deletion and, as a result of treatment with exogenous GH, have developed neutralizing antibodies that render further GH therapy ineffective.[2]

It is explicitly stated that mecasermin is not a substitute for GH therapy in its approved indications. Furthermore, it is not intended for the treatment of secondary forms of IGF-1 deficiency, which may arise from conditions such as GH deficiency, malnutrition, hypothyroidism, or the chronic use of pharmacologic doses of corticosteroids. These underlying conditions must be identified and corrected before considering mecasermin therapy.[2]

The clinical efficacy of mecasermin in this target population is well-established and profound. The regulatory approvals were based on data from several open-label clinical trials involving children with SPIGFD. In a pivotal pooled analysis of 76 children, treatment with mecasermin resulted in a dramatic acceleration of growth. The mean height velocity increased from a baseline rate of 2.8 cm/year to 8.0 cm/year during the first year of therapy.[7] This nearly threefold increase in growth rate is a highly significant and clinically meaningful outcome for children facing extreme short stature. Follow-up data showed that growth velocities remained elevated above baseline for up to eight years of continuous treatment, leading to substantial gains in final adult height.[7][ This large effect size was a critical factor in its approval, as it provided a clear and compelling benefit that could be weighed against the drug's significant safety considerations. For a niche therapy with inherent risks, demonstrating such a transformative benefit is essential for establishing a favorable risk-benefit profile.]

Investigational and Off-Label Applications

[Beyond its approved indication, mecasermin has been investigated for other conditions, with Rett Syndrome being the most prominent example.]

Rett Syndrome (RTT): Rett Syndrome is a severe neurodevelopmental disorder caused by mutations in the MECP2 gene. Preclinical studies in mouse models of RTT provided a strong rationale for investigating IGF-1 as a potential therapy. These studies suggested that IGF-1 could reverse many of the synaptic and neuronal deficits seen in the disorder, leading to improvements in behavior, respiratory function, and motor skills.[3][ This led to a clinical development program in humans.]

A Phase 1 open-label, multiple ascending dose trial (NCT01253317) was conducted in 12 girls with RTT.[23] The study successfully met its primary objectives, demonstrating that mecasermin was safe and generally well-tolerated in this population. A key finding from this trial was the confirmation of target engagement within the central nervous system (CNS). Analysis of cerebrospinal fluid (CSF) showed a significant increase in IGF-1 levels following treatment, confirming that the drug could cross the blood-brain barrier and reach its intended site of action.[23] Preliminary efficacy data from the open-label extension phase were encouraging, suggesting potential improvements in some of the core symptoms of RTT, including breathing abnormalities (apnea), anxiety, and mood.[23]

However, the promise of these early findings was not realized in a subsequent, more rigorous Phase 2 placebo-controlled, crossover trial (NCT01777542) involving 30 girls with RTT.[27] This pivotal study failed to demonstrate a statistically significant difference between mecasermin and placebo on its primary clinical endpoints. In fact, some secondary measures, including certain EEG parameters and mood scale scores, suggested a worsening of symptoms with active treatment.[28]

The Rett Syndrome program serves as a salient example of the challenges inherent in translating preclinical findings from animal models to clinical efficacy in humans, particularly for complex neurodevelopmental disorders. The Phase 1 trial successfully validated the pharmacological hypothesis—that systemically administered mecasermin could increase IGF-1 levels in the CNS. However, the Phase 2 trial demonstrated that this biological effect did not translate into a meaningful clinical benefit. This outcome suggests that the pathophysiology of Rett Syndrome is likely far more complex than a simple deficiency of IGF-1 signaling, and that the downstream consequences of the MECP2[ mutation may not be readily reversible by this specific therapeutic modality. This highlights a critical gap that often exists between successful target engagement and the achievement of a desired clinical outcome in CNS drug development.]

Other Potential Uses:[ Mecasermin has also been explored in other clinical areas, leveraging its metabolic and anabolic properties.]

• Diabetes Mellitus: Completed Phase 3 clinical trials have investigated its use in diabetes, presumably to take advantage of its potent insulin-like, glucose-lowering effects.[6]
• Anorexia Nervosa: A completed Phase 3 trial evaluated mecasermin in patients with anorexia nervosa. The rationale may have been to address the loss of bone mass and other metabolic derangements associated with severe malnutrition.[7]
• Amyotrophic Lateral Sclerosis (ALS): Preclinical studies have suggested a potential neuroprotective role for IGF-1, leading to its consideration as a treatment for ALS.[6]

Safety, Tolerability, and Risk Management

[The clinical use of mecasermin is governed by a comprehensive understanding of its safety profile. The adverse effects are largely predictable consequences of IGF-1's potent physiological actions.]

Adverse Reactions

[The incidence and nature of adverse reactions have been well-characterized in clinical trials and post-marketing surveillance.]

System Organ Class	Frequency	Adverse Event	Source
Endocrine/Metabolic	Very Common (>10%)	Hypoglycemia	14
	Common (1-10%)	Severe Hypoglycemia, Hypoglycemic Seizure, Loss of Consciousness	14
Nervous System	Common (1-10%)	Headache, Dizziness, Convulsion	14
	Post-Marketing	Intracranial Hypertension	8
Immune System / General	Very Common (>10%)	Tonsillar Hypertrophy	14
	Common (1-10%)	Thymus Hypertrophy	14
	Less Common (<1%)	Anaphylaxis, Generalized Urticaria, Angioedema	32
Local Site Reactions	Common (1-10%)	Lipohypertrophy, Bruising at injection site	14
Cardiovascular	Common (1-10%)	Cardiac Murmur	14
Musculoskeletal	Common (1-10%)	Arthralgia (Joint Pain)	14
	Post-Marketing	Osteonecrosis/Avascular Necrosis (assoc. with SCFE)	32
Ear and Labyrinth	Common (1-10%)	Otitis Media	14
Neoplasms	Post-Marketing	Benign and Malignant Neoplasms	32

[The safety profile of mecasermin is a direct reflection of the fundamental biology of IGF-1. The constellation of common and serious adverse events is not a series of random toxicities but rather a coherent set of outcomes stemming from the drug's powerful, systemic physiological effects. IGF-1 is a potent insulin-like molecule, which logically leads to hypoglycemia as the primary dose-limiting toxicity. It is a powerful mitogen and growth factor for all tissues, which explains the risks of lymphoid tissue hypertrophy (tonsils, adenoids), the potential for progression of scoliosis during rapid catch-up growth, and the theoretical concern regarding neoplasia. The occurrence of slipped capital femoral epiphysis (SCFE) is also a known complication of any therapy that induces rapid linear growth in susceptible children. Therefore, managing the safety of mecasermin therapy is synonymous with managing the physiological consequences of restoring or inducing supraphysiological levels of IGF-1 activity.]

Warnings, Precautions, and Contraindications

[Due to its potent biological effects, the use of mecasermin is accompanied by several significant warnings and precautions.]

• Hypoglycemia: This is the most immediate and frequent risk. Mecasermin's insulin-like effects can lead to severe hypoglycemia, which may manifest as seizures or loss of consciousness.[2][ Rigorous adherence to administration guidelines concerning meals is the primary strategy for mitigating this risk.]
• Neoplasia: As a potent growth factor that promotes cell proliferation and survival, there is a theoretical risk that mecasermin could promote the growth of existing neoplasms or contribute to the development of new ones. Post-marketing cases of both benign and malignant neoplasms have been reported in pediatric patients receiving treatment, although a definitive causal link has not been established.[2] The risk may be elevated in patients who receive doses higher than recommended or are treated for unapproved indications.[9]
• Intracranial Hypertension (IH): Similar to reports with GH therapy, cases of IH (also known as pseudotumor cerebri) have occurred in patients treated with mecasermin. Symptoms include papilledema, visual changes, persistent headache, nausea, and vomiting. Funduscopic examination of the eyes is recommended at the start of therapy and periodically thereafter to screen for this complication.[8]
• Lymphoid Tissue Hypertrophy: Mecasermin can stimulate the growth of lymphoid tissue, leading to tonsillar and/or adenoidal hypertrophy. This can result in clinical complications such as snoring, obstructive sleep apnea, and chronic middle-ear effusions requiring medical or surgical intervention.[2]
• Skeletal Complications: Children undergoing rapid "catch-up" growth are at an increased risk for slipped capital femoral epiphysis (SCFE). Any child on mecasermin therapy who develops a limp or complains of hip or knee pain should be promptly evaluated for this condition. Additionally, rapid growth can cause the progression of pre-existing scoliosis.[2]
• Benzyl Alcohol Preservative: The multi-dose vial formulation of Increlex contains benzyl alcohol as a preservative. Large amounts of benzyl alcohol have been associated with a fatal toxicity known as "gasping syndrome" in neonates and premature infants. Therefore, its use in this population is cautioned against.[14]

Contraindications:[ The use of mecasermin is strictly contraindicated in several situations:]

• Active or Suspected Neoplasia: It should not be used in patients with an active or suspected malignancy, or in those with a history of malignancy.[2]
• Closed Epiphyses: Once a child's epiphyseal growth plates have fused, they have reached their final adult height, and there is no potential for further linear growth. Use of mecasermin in this population is contraindicated as it offers no benefit and only exposes the patient to risks.[2]
• Known Hypersensitivity: The drug is contraindicated in patients with a known hypersensitivity to mecasermin or any of its excipients.[2]
• Intravenous Administration: Mecasermin must only be administered subcutaneously; intravenous administration is contraindicated.[18]

Notably, despite the severity of these potential risks, regulatory documents indicate that mecasermin does not carry a "black box" warning in its labeling.[21][ This absence is a significant regulatory statement. It suggests that agencies like the FDA have judged that the risks, while serious, are predictable and can be adequately managed through the comprehensive warnings, precautions, and highly specific risk management protocols detailed in the product label. This implies a determination that for the intended, well-defined patient population with a high unmet medical need, the substantial benefits of treatment outweigh the manageable risks, provided that therapy is prescribed and overseen by specialists who adhere strictly to the established guidelines.]

Drug-Drug Interactions

[The most clinically significant drug-drug interactions with mecasermin are pharmacodynamic in nature and relate to its effects on glucose metabolism.]

Interacting Drug Class	Example Drugs	Mechanism of Interaction	Clinical Management Recommendation
Insulins	Insulin aspart, insulin glargine, regular human insulin	Pharmacodynamic synergism	Increased risk of hypoglycemia. Monitor blood glucose closely. A reduction in insulin dosage may be required.
Sulfonylureas	Glipizide, glyburide, glimepiride	Pharmacodynamic synergism	Increased risk of hypoglycemia. Monitor blood glucose closely. A reduction in sulfonylurea dosage may be required.
Other Hypoglycemic Agents	Acarbose, albiglutide, nateglinide	Pharmacodynamic synergism	Increased risk of hypoglycemia. Monitor blood glucose closely.
Corticosteroids	Betamethasone, alclometasone	Pharmacodynamic antagonism	Increased risk of hyperglycemia; may decrease the therapeutic efficacy of mecasermin. Monitor blood glucose and growth response.
Beta-2 Adrenergic Agonists	Albuterol	Pharmacodynamic antagonism	May decrease the therapeutic efficacy of mecasermin by increasing blood glucose. Monitor growth response.
Tricyclic Antidepressants	Amitriptyline, amoxapine	Pharmacodynamic antagonism	May decrease the hypoglycemic activities of mecasermin. Monitor blood glucose.

There are at least 24 drugs known to have moderate interactions with mecasermin, the vast majority of which either potentiate its hypoglycemic effect or antagonize its therapeutic action.[37][ Co-administration with any agent that affects blood glucose requires careful monitoring and potential dose adjustments.]

Dosage, Administration, and Patient Monitoring

[The safe and effective use of mecasermin requires strict adherence to specific guidelines for dosing, administration, and patient monitoring.]

Dosing Regimen

[The dosage of mecasermin must be individualized for each patient based on body weight, clinical response, and tolerance.]

• Initial Dose: Treatment should be initiated at a starting dose of 0.04 to 0.08 mg/kg of body weight.[8]
• Frequency: This dose is administered twice daily.[8]
• Dose Titration: If the initial dose is well-tolerated for at least one week (i.e., without significant hypoglycemia), the dose may be increased by an increment of 0.04 mg/kg per dose.[8]
• Maximum Dose: The dose should be titrated upwards as tolerated to a maximum of 0.12 mg/kg twice daily. Doses exceeding this maximum have not been evaluated in clinical trials for SPIGFD and should not be used, as they may unacceptably increase the risk of hypoglycemia and other adverse effects, including neoplasia.[11]
• Dose Reduction: If a patient experiences recurrent or severe hypoglycemia at a given dose despite adequate food intake, the dose should be reduced.[8]

Formulation and Administration

[Proper administration technique is critical to the safety and efficacy of mecasermin therapy.]

• Formulation: Increlex is supplied as a sterile, clear, and colorless 10 mg/mL solution in a 4 mL multi-dose glass vial (40 mg total per vial).[8] The solution should be visually inspected before each use; it should not be administered if it is cloudy or contains particulate matter.[17]
• Route of Administration: Mecasermin is for subcutaneous injection only. It must never be administered intravenously.[17]
• Injection Site Rotation: To prevent lipohypertrophy (a localized buildup of fatty tissue), injection sites should be systematically rotated with each dose. Recommended sites include the upper arms, thighs, buttocks, and abdomen.[8]
• Storage: Vials should be stored under refrigeration, protected from light, and must not be frozen. After the first use, an opened vial must be discarded after 30 days, regardless of the remaining volume.[20]

The administration guidelines for mecasermin represent a core safety protocol, not merely a set of procedural instructions. The most critical aspect is the timing of the injection relative to food intake. The dose must be administered shortly before or after (within a 20-minute window) a meal or snack.[2][ This strict requirement is a direct clinical countermeasure designed to mitigate the drug's potent and predictable hypoglycemic effect. By ensuring that an exogenous supply of carbohydrates is available to coincide with the drug's peak glucose-lowering action, the risk of a dangerous drop in blood sugar is significantly reduced. Consequently, if a patient is unable to eat for any reason, the corresponding dose of mecasermin]

must be withheld. Furthermore, subsequent doses should never be increased to compensate for a missed dose.[2][ Adherence to this protocol is the primary factor that separates a therapeutic dose from a potentially dangerous one.]

Essential Patient Monitoring

[Ongoing and comprehensive patient monitoring is an integral part of mecasermin therapy.]

• Glucose Monitoring: At the initiation of therapy, preprandial (before meal) blood glucose monitoring is recommended until a stable, well-tolerated dose is established. Monitoring should be continued if the patient experiences frequent symptoms of hypoglycemia or any episode of severe hypoglycemia.[2]
• Ophthalmological Monitoring: To screen for the potential development of intracranial hypertension, a funduscopic examination by an ophthalmologist is recommended at the start of therapy and periodically thereafter.[8]
• Physical Examination: Regular physical examinations should be conducted to monitor for potential complications. This includes checking for signs of lymphoid tissue hypertrophy (e.g., assessing for snoring, sleep apnea, or chronic middle-ear effusions), monitoring patients with a history of scoliosis for progression of the spinal curve, and evaluating for any new or changing neoplasms.[2]
• Cardiovascular Monitoring: An echocardiogram is recommended for all patients prior to initiating treatment to establish a baseline cardiac status.[11]
• Growth Assessment: The therapeutic response should be monitored by regularly measuring height and calculating height velocity. A failure to increase height velocity by at least 2 cm/year during the first year of treatment should prompt a thorough re-evaluation, including an assessment of patient compliance with the regimen and an investigation into other potential causes of growth failure.[21]

Regulatory and Developmental History

[The regulatory pathway of mecasermin reflects the specific challenges and considerations associated with developing therapies for rare diseases.]

U.S. Food and Drug Administration (FDA) Pathway

The development and approval of Increlex in the United States were sponsored by Tercica, Inc..[41][ The key milestones in its regulatory journey were:]

• February 28, 2005: Tercica submitted a New Drug Application (NDA) to the FDA for mecasermin as a treatment for short stature caused by Primary IGF-1 Deficiency.[41]
• May 2, 2005: The FDA accepted the NDA for review and granted it Priority Review status, a designation reserved for drugs that may offer significant improvements in the treatment of serious conditions.[41]
• August 30, 2005: Increlex (mecasermin) received final marketing approval from the FDA.[41]

The approved indication was for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH.[41]

European Medicines Agency (EMA) Pathway

[In Europe, mecasermin also followed a specialized regulatory path tailored for rare diseases.]

• Orphan Drug Designation: On May 22, 2006, the EMA designated Increlex as an 'orphan medicine'. This status is granted to drugs intended for the treatment of rare, life-threatening, or chronically debilitating conditions, providing incentives for their development.[22]
• Marketing Authorisation: The European Commission granted a marketing authorisation valid throughout the European Union on August 3, 2007.[22]
• Authorisation under "Exceptional Circumstances": The approval was granted under the 'exceptional circumstances' provision. This pathway is used when a comprehensive data package on efficacy and safety cannot be provided at the time of authorisation under normal conditions of use, typically because the disease is so rare that conducting large-scale, conventional clinical trials is not feasible. This acknowledges the practical difficulties of drug development in this space while still allowing patient access to a needed therapy.[22]

The EMA-approved indication is for the long-term treatment of growth failure in children and adolescents from 2 to 18 years of age with confirmed severe primary IGF-1 deficiency.[11]

The Case of Mecasermin Rinfabate (Iplex)

The developmental history of mecasermin rinfabate (Iplex), the complex of rhIGF-1 and rhIGFBP-3, provides an instructive contrast. While developed for a similar indication, its regulatory journey in Europe had a different outcome. The marketing authorisation application for Iplex was formally withdrawn by its sponsor on March 26, 2007. This withdrawal followed an evaluation by the EMA's Committee for Medicinal Products for Human Use (CHMP), which had concluded that, based on the clinical data submitted at that time, the benefits of Iplex had not been sufficiently demonstrated to outweigh its identified risks.[44]

[The divergent regulatory outcomes for Increlex and Iplex, two closely related therapies for the same rare condition, offer a valuable perspective on the regulatory process for orphan drugs. The approval of Increlex under "exceptional circumstances" demonstrates a regulatory flexibility designed to address high unmet medical needs in diseases where comprehensive data collection is inherently challenging. However, the withdrawal of the Iplex application shows that this flexibility is not unlimited. The risk-benefit assessment remains paramount, and the clinical evidence, even if limited, must still be compelling enough to support a positive conclusion. This juxtaposition illustrates the fine line that regulatory agencies must navigate in the orphan drug landscape: balancing the imperative to facilitate patient access to novel therapies with the fundamental responsibility to uphold rigorous standards of safety and efficacy.]

Expert Synthesis and Concluding Remarks

[Mecasermin (Increlex) stands as a significant achievement in targeted biopharmaceutical therapy. It provides a highly effective, life-altering treatment for a precisely defined and vulnerable pediatric population: children with severe growth failure resulting from primary IGF-1 deficiency. For these patients, in whom conventional growth hormone therapy is ineffective, mecasermin offers a direct and potent mechanism to restore a critical physiological pathway, leading to profound and sustained improvements in linear growth. Its efficacy within this specific niche is both dramatic and undeniable.]

[However, the clinical profile of mecasermin is characterized by an intrinsic and inescapable duality. Its powerful, on-target mechanism of action—the very source of its remarkable therapeutic benefit—is simultaneously the source of its most significant and predictable risks. The drug's potent anabolic effects on skeletal and somatic growth are inextricably linked to its equally potent insulin-like effects on glucose metabolism. Consequently, the clinical management of mecasermin is a continuous exercise in balancing these two facets of its pharmacology, maximizing growth while minimizing the ever-present risk of hypoglycemia.]

[This duality elevates the importance of the drug's administration and monitoring protocols. The stringent guidelines—particularly the non-negotiable requirement to administer each dose in close temporal proximity to a meal or snack—are not merely ancillary instructions. They represent a core clinical risk management strategy that is embedded directly into the therapeutic regimen itself. Adherence to this protocol is the principal determinant of the drug's acute safety.]

[The attempts to expand mecasermin's therapeutic utility beyond SPIGFD, most notably in the clinical trials for Rett Syndrome, serve as a modern cautionary tale in translational medicine. These studies demonstrated that even with a robust preclinical rationale, a well-understood mechanism of action, and confirmed target engagement within the central nervous system, translating these pharmacological successes into meaningful clinical efficacy for a complex neurodevelopmental disorder remains a formidable and often elusive goal.]

[In conclusion, mecasermin is best understood as a highly specialized and powerful therapeutic tool, not a broad-spectrum growth or metabolic agent. Its regulatory journey, marked by orphan drug designations and approvals under exceptional circumstances, underscores the evolving regulatory landscape for rare disease therapies. Mecasermin will undoubtedly remain a cornerstone of treatment for children with SPIGFD, a testament to its targeted design and profound impact. Its future likely lies not in broad indication expansion, but in the continued refinement of its use within this well-defined therapeutic window, where its substantial benefits can be realized while its inherent risks are meticulously managed.]

Works cited

1. Mecasermin - Wikipedia, accessed August 27, 2025, https://en.wikipedia.org/wiki/Mecasermin
2. Mecasermin Monograph for Professionals - Drugs.com, accessed August 27, 2025, https://www.drugs.com/monograph/mecasermin.html
3. Recombinant Human IGF-I - Mecasermin - MedchemExpress.com, accessed August 27, 2025, https://www.medchemexpress.com/mecasermin.html
4. What is the mechanism of Mecasermin? - Patsnap Synapse, accessed August 27, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-mecasermin
5. Mecasermin - brand name list from Drugs.com, accessed August 27, 2025, https://www.drugs.com/ingredient/mecasermin.html
6. Mecasermin | 68562-41-4 - ChemicalBook, accessed August 27, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB51179104.htm
7. Mecasermin - PubMed, accessed August 27, 2025, https://pubmed.ncbi.nlm.nih.gov/18481900/
8. INCRELEX® Full prescribing Information - Ipsen, accessed August 27, 2025, https://www.ipsen.com/websites/Ipsen_Online/wp-content/uploads/sites/9/2020/04/10140519/Increlex-Full-Prescribing-Information.pdf
9. INCRELEX® (Mecasermin) Injection Official Site, accessed August 27, 2025, https://www.increlex.com/en-us
10. INCRELEX, INN: mecasermin - EMA, accessed August 27, 2025, https://www.ema.europa.eu/en/documents/scientific-discussion/increlex-epar-scientific-discussion_en.pdf
11. Increlex, INN-mecasermin - European Medicines Agency, accessed August 27, 2025, https://www.ema.europa.eu/en/documents/product-information/increlex-epar-product-information_en.pdf
12. Mecasermin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01277
13. Union Register of medicinal products - Public health - European Commission, accessed August 27, 2025, https://ec.europa.eu/health/documents/community-register/html/h402.htm
14. Mecasermin | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 27, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/6043/Mecasermin
15. Mecasermin for primary insulin-like growth factor-1 deficiency - PMC, accessed August 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9722352/
16. Mecasermin rinfabate: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 27, 2025, https://go.drugbank.com/drugs/DB14751
17. Label: INCRELEX- mecasermin injection, solution - DailyMed, accessed August 27, 2025, https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a8b27a1b-a611-4f91-ad22-76d4b390c3ae
18. 1 PACKAGE INSERT IPLEX™ (mecasermin ... - accessdata.fda.gov, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021884s001lbl.pdf
19. Annotation of EMA Label for mecasermin and IGF1 - ClinPGx, accessed August 27, 2025, https://www.clinpgx.org/labelAnnotation/PA166353101
20. Mecasermin Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 27, 2025, https://www.drugs.com/dosage/mecasermin.html
21. ERX.SPA.209 Mecasermin (Increlex) - Meridian Medicare Medicaid Plan, accessed August 27, 2025, https://mmp.ilmeridian.com/content/dam/centene/meridian/il/pdf/Mecasermin%20(Increlex)%2009.01.21.pdf
22. Increlex | European Medicines Agency (EMA), accessed August 27, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/increlex
23. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome - PubMed Central, accessed August 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3970488/
24. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome | PNAS, accessed August 27, 2025, https://www.pnas.org/doi/10.1073/pnas.1311141111
25. Study Details | Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection), accessed August 27, 2025, https://www.clinicaltrials.gov/study/NCT01253317?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(MECASERMIN))))&rank=2
26. Study Details | Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection), accessed August 27, 2025, https://www.clinicaltrials.gov/study/NCT01253317
27. Study Details | Treatment of Rett Syndrome With Recombinant Human IGF-1, accessed August 27, 2025, https://www.clinicaltrials.gov/study/NCT01777542
28. Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome, accessed August 27, 2025, https://pubmed.ncbi.nlm.nih.gov/29560377/
29. Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome, accessed August 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5846450/
30. Mecasermin Completed Phase 3 Trials for Diabetes Mellitus | DrugBank Online, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01277/clinical_trials?conditions=DBCOND0027886&phase=3&status=completed
31. Mecasermin Completed Phase 3 Trials for Anorexia Nervosa (AN) Treatment - DrugBank, accessed August 27, 2025, https://go.drugbank.com/drugs/DB01277/clinical_trials?conditions=DBCOND0052289&phase=3&purpose=treatment&status=completed
32. Increlex (mecasermin) dosing, indications, interactions, adverse effects, and more, accessed August 27, 2025, https://reference.medscape.com/drug/increlex-mecasermin-342798
33. Mecasermin: Side Effects, Uses, Dosage, Interactions, Warnings, accessed August 27, 2025, https://www.rxlist.com/mecasermin/generic-drug.htm
34. Learn how INCRELEX® (mecasermin) could help your child, accessed August 27, 2025, https://www.increlex.com/en-us/about-increlex
35. Mecasermin (subcutaneous route) - Side effects & dosage - Mayo Clinic, accessed August 27, 2025, https://www.mayoclinic.org/drugs-supplements/mecasermin-subcutaneous-route/description/drg-20068117
36. INCRELEX® to Treat Severe Primary IGF-1 Deficiency, accessed August 27, 2025, https://www.increlex.com/en-us/hcp/increlex-for-spigfd
37. Mecasermin Interactions Checker - Drugs.com, accessed August 27, 2025, https://www.drugs.com/drug-interactions/mecasermin.html
38. Mecasermin rinfabate Interactions - Drugs.com, accessed August 27, 2025, https://www.drugs.com/drug-interactions/mecasermin-rinfabate.html
39. Increlex Interactions Checker - Drugs.com, accessed August 27, 2025, https://www.drugs.com/drug-interactions/mecasermin,increlex.html
40. Mecasermin Uses, Side Effects & Warnings - Drugs.com, accessed August 27, 2025, https://www.drugs.com/mtm/mecasermin.html
41. Increlex (mecasermin) FDA Approval History - Drugs.com, accessed August 27, 2025, https://www.drugs.com/history/increlex.html
42. Drug Approval Package: Increlex (Mecasermin [rDNA origin]) NDA #021839, accessed August 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021839_IncrelexTOC.cfm
43. Human medicines European public assessment report (EPAR): Increlex, mecasermin, Date of authorisation: 02/08/2007, Revision: 26, Status, accessed August 27, 2025, https://efim.org/node/140903
44. Iplex | European Medicines Agency (EMA), accessed August 27, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/iplex