EU/3/06/373: Orphan designation for the treatment of primary insulin-like growth factor-1 deficiency due to molecular or genetic defects

Insulin-like growth factor-1 (IGF-1) is a naturally occurring hormone secreted (produced) in the body which, together with growth hormone (GH), plays a central role in stimulating growth of the human body. Deficiency of IGF-1 results in short stature (height) and can be caused by an underlying molecular or genetic defect. There may be molecular defects in the specific structures on the surface of cells (receptors) that GH binds to, resulting in resistance to GH, or signalling defects in the cascade of molecular reactions which induce (stimulate) the biological activity of growth, or defects in expression of the gene that codes for production of IGF-1. In these cases the primary deficiency is circulating IGF-1, with GH levels being normal or elevated. The reason why these molecular or genetic defects occur is unknown.

Primary insulin-like growth factor-1 deficiency due to molecular or genetic defects is a serious and chronically debilitating condition.

At the time of designation primary insulin-like growth factor-1 deficiency due to molecular or genetic defects affected less than 2 in 10,000 people in the European Union (EU) *. This is based on the information provided by the sponsor and knowledge of the Committee for Orphan Medicinal Products (COMP). This is below the threshold for orphan designation which is 5 in 10,000. This is equivalent to a total of around 90,000 people.

* Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed based on data from the European Union (EU 25), Norway, Iceland and Liechtenstein. This represents a population of 459,700,000 (Eurostat 2004).

There were no approved treatments for primary insulin-like growth factor-1 deficiency at the time of designation.

Mecasermin is a recombinant (artificially synthesised) human insulin-like growth factor-1. Once administered in patients with primary IGF-1 deficiency, mecasermin is expected to replace the natural IGF-1 in the body, thus compensating for its loss. Thus, mecasermin is expected to stimulate the growth of the body in the same way as IGF-1.

The effects of mecasermin were evaluated in experimental models. At the time of submission of the application for orphan designation, clinical trials in patients with primary insulin-like growth factor-1 deficiency were ongoing.

Mecasermin was authorised as an orphan medicinal product in the USA for 'the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone', at the time of submission.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 5 April 2006 a positive opinion recommending the grant of the above-mentioned designation.

Update: Mecasermin (Increlex) has been authorised in the EU since 3 August 2007 for the long-term treatment of growth failure in children and adolescents with severe primary insulin-like growth factor-1 deficiency (primary IGFD). Severe primary IGFD is defined by:

• height standard deviation score ≤ –3.0 and
• basal IGF-1 levels below the 2.5th percentile for age and gender and GH sufficiency.
• exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.

Severe primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment. It is recommended to confirm the diagnosis by conducting an IGF-1 generation test.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.