Medical Policy



Subject: Mecasermin (Increlex®)
Document #: DRUG.00086 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of mecasermin (Increlex® ), a recombinant human insulin-like growth factor-1 (rhIGF-1) drug, proposed for the treatment of conditions related to IGF-1 deficiency (IGFD) and other forms of growth hormone insensitivity.

Note: For information related to growth hormone therapy, please see:

Position Statement

Medically Necessary:

Use of mecasermin (Increlex) is considered medically necessary for the treatment of individuals greater than 2 years of age with the following indications:

  1. Growth failure in children with severe primary IGF-1 deficiency, as defined by:
    1. Height standard deviation (SD) score less than or equal to –3.0; and
    2. Basal IGF-1 SD score less than or equal to –3.0; and
    3. Normal or elevated growth hormone (GH) levels (greater than 10 ng/ml on standard GH stimulation tests, see DRUG.00009 for additional information) are present; or
  2. Growth hormone gene deletion with the development of neutralizing antibodies to GH.

Continuation of treatment with mecasermin (Increlex) is considered medically necessary when the following criteria have been met:

  1. Growth velocity is greater than or equal to 2 cm total growth in 1 year; and
  2. Final adult height has not been reached.

Not Medically Necessary:

Use of mecasermin (Increlex) is considered not medically necessary for individuals with the following contraindications:

  1. Closed epiphyses; or
  2. Suspected or known malignancies.

Investigational and Not Medically Necessary:

Use of mecasermin (Increlex) is considered investigational and not medically necessary for the treatment of all other indications, including but not limited to:

  1. When any of the medically necessary indications above are not present; or
  2. Growth velocity is less than 2 cm total growth in 1 year; or
  3. Final adult height has been reached; or
  4. Secondary IGFD (for example, due to GH deficiency, untreated malnutrition, untreated hypothyroidism or other causes).
Rationale

The U.S. Food & Drug Administration (FDA) has approved mecasermin for two indications involving growth failure in children. The first indication is for severe primary IGF-1 deficiency (IGFD), and the second is for individuals with growth hormone (GH) gene deletion with the development of neutralizing antibodies to GH.

There are no currently available studies in the peer-reviewed published literature that describe a clinical trial of mecasermin for these indications. However, the FDA submission data included evidence from five different trials (four open label and one double-blinded, placebo controlled) involving a total of 71 subjects with primary IGDF followed for up to 8 years. The investigators reported that mecasermin administration resulted in significantly increased height velocity for up to 6 years of treatment, compared to baseline. In the first year, height velocity more than doubled and went from a mean of 2.8 ± 1.8 cm/yr to 8.0 ± 2.2 cm/yr (p<0.0001). In follow-up years 2 through 6, height velocities were 5.8, 5.5, 4.7, 4.7, and 4.8 cm/yr, (p<0.0001, p<0.0001, p<0.0045, p<0.0015, and p<0.0009, respectively). Similar results were found when looking at height standard deviations score (SDS) (p<0.0001 for years 1 through 5; p<0.0003 for year 6). Most of the increases in height SDS were gained by the third year and maintained through the end of the trial. The investigators reported that there were several adverse events (AEs) that were considered to be "possibly related" to mecasermin treatment. These included severe tonsillar hypertrophy; moderately severe tricuspid insufficiency associated with right ventricular hypertrophy, seizures potentially related to hypoglycemia, progression of retinopathy, sleep apnea, pulmonary hypertension, cardiomegaly, renal calculus, and papilledema/headache/Arnold-Chiari malformation. Other AEs of note include the reported emergent treatment hypoglycemia, lymphoid tissue hypertrophy, pseudotumor cerebri, retinopathy, and organ growth.

The FDA approved prescribing information for mecasermin lists active or known neoplasia and closed epiphyses as contraindications to its use. This is due to concerns with regard to potential significant risks to the health of the treated individual.

Use of mecasermin has been investigated for a wide array of indications, including acute renal failure, amyotrophic lateral sclerosis, anorexia nervosa, Laron syndrome, myotonic dystrophy, periodontal disease, Rett syndrome, and type I diabetes (Borasio, 1998; Guevara-Aguirre, 1995; Hirschberg, 1999; Khwaja, 2014; Lai, 1997; Quattrin, 1997; Quattrin, 2001; Thrailkill, 1999; Vlachopapadopoulou, 1995). However, the evidence addressing these indications is limited to a small number of trials with limited generalizability. Furthermore, most of these investigations were conducted over a decade ago with no further studies published and many, like those addressing the use of mecasermin for diabetes, had negative or equivocal conclusions regarding clinical benefit.

Background/Overview

Teissier (2014), using a large population-based study and the standard criterion for rhIGF1 treatment, estimated the prevalence of severe primary IGFD to be 1.2% of children reporting for evaluation of short stature.

Mecasermin (Increlex) contains recombinant human insulin-like growth factor-1 (rhIGF-1). The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.

The FDA approval language for this drug states it is indicated for the treatment of the following indications:

The FDA approved label clarifies that severe primary IGFD is defined by:

Growth hormone insensitivity syndrome (GHI) or insulin-like growth factor-1 (IGF-1) deficiency (IGFD) is characterized by deficit of IGF-1 production due to alteration of response of growth hormone (GH) receptor to GH. This syndrome is due to mutation of GH receptor or IGF-1 gene. Individuals with IGFD are not GH deficient, and do not respond to exogenous GH treatment. The only treatment is recombinant IGF-1 (mecasermin).

Mecasermin is not intended for use in individuals with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment.

Another drug containing mecasermin has also been approved by the FDA. Iplex® (mecasermin rinfinabate) was approved for the same indications as Increlex. However, Iplex has not been available in the U.S. since 2009 and according to the manufacturer, it has been discontinued.

Definitions

Severe primary IGFD: A condition characterized by basal IGF-1 standard deviation score (SDS) less than or equal to −3 and height SDS less than or equal to −3 in a child with normal or elevated levels of growth hormone. This condition may include individuals with mutations in the GH receptor (GHR), post-GHR signaling pathway or IGF-1 gene defects.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS  
J2170 Injection, mecasermin, 1 mg [Increlex]
   
ICD-10 Diagnosis    
E34.3 Short stature due to endocrine disorder  
R62.52 Short stature (child)  

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when contraindications listed in the Position Statement section are present.

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Borasio GD, Robberecht W, Leigh PN, et al. A placebo-controlled trial of insulin-like growth factor-1 in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology. 1998; 51(2):583-586.
  2. Guevara-Aguirre J, Vasconez O, Martinez V, et al. A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 1995; 80(4):1393-1398.
  3. Hirschberg R, Kopple J, Lipsett P, et al. Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int. 1999; 55(6):2423-2432.
  4. Khwaja OS, Ho E, Barnes KV, et al. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014; 111(12):4596-4601.
  5. Lai EC, Felice KJ, Festoff BW, et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology. 1997; 49(6):1621-1630.
  6. Quattrin T, Thrailkill K, Baker L, et al. Dual hormonal replacement with insulin and recombinant human insulin-like growth factor I in IDDM. Effects on glycemic control, IGF-I levels, and safety profile. Diabetes Care. 1997; 20(3):374-380.
  7. Quattrin T, Thrailkill K, Baker L, et al.; rhIGF-I in IDDM Study Group. Improvement of HbA1c without increased hypoglycemia in adolescents and young adults with type 1 diabetes mellitus treated with recombinant human insulin-like growth factor-I and insulin. J Pediatr Endocrinol Metab. 2001; 14(3):267-277.
  8. Teissier R, Flechtner I, Colmenares A, et al. Characterization and prevalence of severe primary IGF1 deficiency in a large cohort of French children with short stature. Eur J Endocrinol. 2014; 170(6):847-854.
  9. Thrailkill KM, Quattrin T, Baker L, et al. Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemic control in type 1 diabetes. RhIGF-I in IDDM Study Group. Diabetes Care. 1999;22(4):585-592.
  10. Vlachopapadopoulou E, Zachwieja JJ, Gertner JM, et al. Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy--a clinical research center study. J Clin Endocrinol Metab. 1995; 80(12):3715-3723.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. United States Food and Drug Administration. Increlex Package Insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021839s016lbl.pdf. Accessed on April 28, 2017.
Index

Increlex
Mecasermin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 05/07/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated formatting in Position Statement section.
New 05/05/2016 MPTAC review. Initial document development.