BlueCross and BlueShield of Montana Medical Policy/Codes
Mecasermin Recombinant (Increlex)
Chapter: Drugs - Medical Benefit
Current Effective Date: August 27, 2013
Original Effective Date: August 27, 2013
Publish Date: May 27, 2013
Description

Mecasermin (rDNA origin) recombinant injection is a synthetic human insulin-like growth factor-1 (IGF-1) that is designed to replace natural IGF-1 in pediatric patients who are deficient, and to promote their normalized statural growth of bones, cells, and internal organs.  Normally, IGF-1 is produced in the liver. 

Severe primary insulin-like growth factor-1 deficiency (IGFD) includes patients with mutations in the growth hormone (GH) receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects.  These patients are not GH deficient, and therefore, cannot be expected to respond effectively to exogenous GH treatment.  The target population is less than 12,000 children worldwide who have a severe IGFD, for whom severe primary IGFD is defined by:

  • Height standard deviation score < -3.0,
  • Basal IGF-1 standard deviation score < -3.0,
  • Normal or elevated GH.

Mecasermin recombinant is not indicated to treat secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or other causes.  It is not a substitute for GH therapy.

Mecasermin recombinant is a DNA-engineered hormone injection that has been manufactured and approved by the U.S. Food and Drug Administration (FDA) as two different orphan drugs:

  • Mecasermin recombinant (subcutaneous) injection (Increlex™) containing only recombinant human (rh) rhIGF-1, approved on August 30, 2005, manufactured by Baxter Pharmaceutical Solutions LLC of Bloomington, Indiana and distributed by Tercica, Inc. of Brisbane, California; and
  • Mecasermin recombinant rinfabate (subcutaneous) injection (Iplex/iPLEX™), containing a binary (two components) protein complex of human rhIGF-1 and human insulin-like growth factor-binding protein-3 (rhIGFBP-3).  The rhIGFBP-3 regulates the release of rhIGF-1 to target tissues as needed, utilizing a longer half-life than Increlex, approved on December 12, 2005, manufactured by Insmed, Inc. of Glen Allen, Virginia.  Effective July 27, 2009, Insmed announced the cease of production of Iplex for all new patients and the remaining supply will be distributed to the treatment of existing patients.  Insmed additionally announced they will not initiate further clinical trials using Iplex.  Therefore, Iplex is no longer available for marketing.

An orphan drug is defined in the 1984 amendments of the Orphan Drug Act as "a drug intended to treat a condition affecting fewer than 200,000 persons in the United States or will not recover development cost, plus a reasonable profit, within seven years following FDA approval.  The Orphan Drug Act was signed into law on January 4, 1983."  

NOTE:  Drug dosing recommendations in the Medical Policy follow FDA approved dosage in the product label.  A prescription for doses that exceed the product label must be accompanied by citation of clinical studies that support a higher dose regimen.

The recommended FDA labeled dosing for Mecasermin Recombinant (Increlex™) states, “Increlex should be administered subcutaneously and injection sites rotated to avoid lipoatrophy; recommended starting dose: 0.04 to 0.08 mg/kg twice daily and if well-tolerated for at least one week: the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily.”

Policy

Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review will be performed if services are not prior authorized.

Medically Necessary

BCBSMT may consider mecasermin recombinant (Increlex™) medically necessary for treatment of growth failure in children with severe primary insulin-like growth factor-1 (IGF-1) deficiency (IGFD) when ALL the following criteria are met:

  • Height standard deviation score £ 3.0, AND
  • Basal IGF-1 standard deviation score £ 3.0, AND
  • Normal or elevated growth hormone (GH) level.

BCBSMT may consider mecasermin recombinant (Increlex™) medically necessary for the treatment of growth failure in children with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.

Investigational

BCBSMT considers all other uses of mecasermin recombinant (Increlex™) experimental, investigational and unproven, including but not limited to the treatment of:

  • GH deficiency (such as Prader-Willi, Russell-Silver, Noonan, or Turner’s syndromes),
  • Short stature due to unknown cause (idiopathic short stature),
  • Malnutrition,
  • Hypothyroidism,
  • Cystic fibrosis,
  • Diabetes,
  • Extreme insulin resistance,
  • Chronic treatment with pharmacologic doses of anti-inflammatory steroids,
  • Myotonic muscular dystrophy (MMD),
  • Amyotrophic lateral sclerosis (ALS),
  • Human immunodeficiency virus- (HIV-) associated adipose redistribution syndrome (HARS) and/or acquired immunodeficiency syndrome- (AIDS-) wasting,
  • Adults with IGF-1 deficiency, OR
  • Retinopathy of prematurity (ROP) in premature neonates.

NOTE:  Iplex™ has been discontinued and is no longer on the market.

NOTE:  See Description for recommended FDA labeled dosing.

Federal Mandate

Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. BCBSMT recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Rationale

According to the manufacturer, it is estimated that 6,000 children in the United States would meet the criteria for coverage using mecasermin.  The FDA approval was based on five studies enrolling a total of 71 patients.  The primary outcomes included changes in height velocity, height velocity standard deviation scores (SDS), and height SDS over a period of eight years.  However, only 13 subjects were followed for the maximum eight-years, and only 58 of the 71 had baseline height velocity data.  Height velocity increased in the first year, on average, to 8.0 cm per year from a baseline height of 2.8 cm per year, nearly tripling the rate of growth (P<0.0001).  In years two through six, height velocity was sustained at approximately 5.0 cm per year.  Change in bone age was appropriate for chronological age.  No final height data was available (FDA, 2005; BCBSA TEC Clearinghouse News, 2006).

In clinical studies of 71 subjects with primary insulin-like growth factor-1 (IGF-1) deficiency (IGFD) treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse events.  Mecasermin has not been studied in children less than two years of age or in adults (FDA, 2005; BCBSA TEC Clearinghouse News, 2006).

2009 Update

Since the last update, additional information was added regarding the new orphan product designation from the FDA approval of mecasermin rinfabate.  The FDA based their decision on a study of 36 children and adolescents with primary insulin-like growth factor-1 deficiency (IGFD).  Subjects were enrolled in the clinical trial on the basis of extremely short stature, low IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3) serum concentrations and normal GH secretion.  The subjects were divided into two cohorts treated sequentially.  Cohort #1 (n=19) were treated for the first 12 months, evaluated at month six and 12, being given up to 1 mg/kg daily.  Cohort #2 (n=17) were evaluated for efficacy at month six after treatment with up to 2 mg/kg daily.  For both cohorts, height velocity increased.  For Cohort #1 subjects at month six, the height velocity increased by 8.1 cm and then increased an additional 6.3 cm at one year.  While on a higher dose level, Cohort #2 subjects had a mean height velocity of 9.1 cm at month six (FDA, 2009).

There have been no studies to date comparing the efficacy of Increlex to Iplex.  According to the literature, mecasermin may have the potential for off-label use in conditions other than severe primary IGFD (Williams, 2008).

Insmed Inc., manufacturer of Iplex, has begun pursuing separate Phase II studies focusing on treatment of both myotonic muscular dystrophy (MMD) and amyotrophic lateral sclerosis (ALS). This is in addition to investigating retinopathy of prematurity (ROP) in premature neonates, via a Material Transfer Agreement with Premacure AB Biopharmaceuticals (Insmed Inc., 2008).

2012 Update

A search of peer reviewed literature and FDA labeling through March 2012 identified no new clinical trial publications or any additional information that would change the Increlex coverage position of this medical policy.  Iplex has been discontinued from marketing based on costs of manufacturing and has been removed from the medically necessary indications of this medical policy (Insmed Inc., 2009).

Coding

Disclaimer for coding information on Medical Policies         

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

783.43

ICD-10 Codes

R62.52

Procedural Codes: J2170
References
  1. American Academy of Pediatrics.  Considerations related to the use of recombinant human growth hormone in children.  American Academy of Pediatrics Committee on Drugs and Committee on Bioethics.  Pediatrics (1997) 99(1):122-9.
  2. Agency for Healthcare Research and Quality.  Evidence Report/Technology Assessment Number 73.  Criteria for determining disability in infants and children: short stature.  (2003 March)
  3. Available at <http://www.ahrg.gov> (accessed on 2006 November 16).
  4. FDA – Increlex (mecasermin recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2005 August 31).  Available at <http://www.fda.gov> (accessed – 2012 April 11).
  5. FDA – Iplex (mecasermin rinfabate recombinant) – Product Information, Label, Approval Letter, News Release.  Food and Drug Administration (2005 December 12).  Available at http://www.fda.gov (accessed – 2012 April 11).
  6. Recombinant Insulin-Like Human Growth Factor-1 Hormone. Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Medical Policy Clearinghouse News.  (2006 March 3).
  7. Kemp, S.F., Fowlkes, J.L., et al.  Efficacy and safety of mecasermin rinfabate.  Expert Opinion on Biological Therapy (2006 May) 6(5):533-8.
  8. Kemp, S.F.  Mecasermin rinfabate.  Drugs Today (Barc) (2007 March) 43(3):149-55.
  9. Keating, G.M.  Mecasermin.  BioDrugs (2008) 22(3):177-88.
  10. Iplex™ - Product Information.  Richmond, Virginia: INSMED Inc. (2008).  Available at http://www.insmed.com (accessed on 2009 November 11).
  11. Williams, R.M., McDonald, A., et al.  Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX.  Expert Opinion on Biological Therapy (2008 March) 4(3):311-24.
  12. Kemp, S.F.  Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: current and future treatment options.  BioDrugs (2009) 23(3):155-63.
  13. Rosenbloom, A.L.  Mecasermin (recombinant human insulin-like growth factor I.  Advances in Therapy (2009 January) 26(1):40-54.
  14. Anonymous.  Mecasermin: new drug.  Insufficient improvement in statural growth.  Prescrire International (2009 June) 18(101):111-3.
  15. Fintini, D., Brufani, C., et al.  Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency.  Journal of Therapeutics and Clinical Risk Management (2009 June) 5(3):553-9.
  16. Iplex – Insmed Provides Update on Supply of IPLEX™ (2009 July 27).  Richmond, Virginia: INSMED Inc. (2009).  Available at http://www.insmed.com (accessed on 2012 April 11).
History
May 2013  New 2013 BCBSMT medical policy.  Possibly investigational.
BCBSMT Home
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Mecasermin Recombinant (Increlex)