INCRELEX - INCRELEX - CT 8906 - English version

Has

Description

Introduction INCRELEX 10 mg/ml, solution for injection B/1 vial of 4 ml (CIP code: 381 467-7) Posted on Jun 22 2011 Active substance (DCI) mecasermin Maladies rares - Mise au point Pas d’avantage clinique pour le traitement du déficit en IGF-1 INCRELEX est indiqué dans le traitement à long terme des retards de croissance chez l’enfant et l’adolescent avec un déficit primaire sévère en IGF-1.Son intérêt thérapeutique reste important lorsque le retard statural est très sévère : ≤ - 4 SDS pour l’âge et le sexe, avec des taux de GH normaux ou élevés :Son intérêt thérapeutique est moins établi lorsque le retard statural est moins sévère (entre -4 et -3 SDS), compte tenu du faible nombre de données et de l’incertitude de l’effet. Pour en savoir plus, téléchargez la synthèse ou l'avis complet de INCRELEX ATC Code H01AC03 Laboratory / Manufacturer IPSEN PHARMA INCRELEX 10 mg/ml, solution for injection B/1 vial of 4 ml (CIP code: 381 467-7) Posted on Jun 22 2011

Sujets

• Pédiatrie
• Maladie génétique
• RARE

Informations

• Publié par: haute-autorite-sante-maladies-endocriniennes-et-metaboliques
• Publié le: 22 juin 2011
• Nombre de lectures: 32
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

Extrait

The legally binding text is the original French version

TRANSPARENCY COMMITTEE

OPINION

22 June 2011


INCRELEX 10 mg/ml, solution for injection
B/1 vial of 4 ml (CIP code: 381 467-7)


Applicant: IPSEN PHARMA

Mecasermin
ATC code: H01AC03 (somatropin and somatropin agonists)

List I
Medicine for hospital prescription restricted to specialists in paediatrics or in endocrinology
and metabolic diseases.
Medicine requiring special monitoring during treatment.
Orphan medicinal product.

Date of Marketing Authorisation: 13/08/2007
Centralised European Marketing Authorisation in exceptional circumstances (the SPC states
that the EMA will review any new information which may become available every year and
this SPC will be updated as necessary).



Reason for examination: Re-assessment in view of new data available in accordance with
the request of the transparency Committee mentioned in the opinion on inclusion dated
05/12/2007.














Medical, Economic and Public Health Assessment Division

1/20

1.

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient
Mecasermin

1.2. Background
First recombinant IGF-1
.
Mecasermin is a recombinant DNA-derived human insulin-like growth factor-1 (IGF-1)
produced inEscherichia coli.

1.3. Indication
“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 (SDS)≤- 3.0 and
• basal IGF-1 levels below the 2.5th percentile for age and gender, and
• GH sufficiency, and
• 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
signalling 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.

1.4. Dosage
“Treatment with INCRELEX should be directed by physicians who are experienced in the
diagnosis and management of patients with growth disorders.
The dosage should be individualised for each patient. The recommended starting dose of
mecasermin is 0.04 mg/kg twice daily by subcutaneous injection. If no significant
treatment-related adverse events occur for at least one week, the dose may be raised in
increments of 0.04 mg/kg to the maximum dose of 0.12 mg/kg given twice daily. Doses
greater than 0.12 mg/kg given twice daily have not been evaluated in children with severe
primary IGFD.
If the recommended dose is not tolerated by the subject, treatment with a lower dosage can
be considered. Treatment success should be evaluated based on height velocities. The
lowest dosage that was associated with substantial growth increases on an individual basis
was 0.04 mg/kg BID.
INCRELEX should be administered shortly before or after a meal or snack. If hypoglycaemia
occurs with recommended doses, despite adequate food intake, the dose should be reduced.
If the patient is unable to eat, for any reason, INCRELEX should be withheld. The dose of
INCRELEX should never be increased to make up for one or more omitted doses.
Injection sites should be rotated to a different site with each injection.
INCRELEX should be administered using sterile disposable syringes and injection needles.
The syringes should be of small enough volume that the prescribed dose can be withdrawn
from the vial with reasonable accuracy.
INCRELEX is not recommended for use in children below age 2 years due to a lack of data
on safety and efficacy.

2/20

2.

SIMILAR MEDICINAL PRODUCTS

2.1. ATC classification
H Systemic hormonal preparations, excluding sex hormones and insulins
H01 Pituitary and hypothalamic hormones and analogues
H01A Anterior pituitary lobe hormones and analogues
H01AC Somatotropin and somatropin agonists
H01AC03 Mecasermin

2.2. Medicines in the same therapeutic category
None

2.3. Medicines with a similar therapeutic aim
There is no other medicinal product which is indicated in the management of severe primary
IGF-1 deficiencies (primary IGFD).

3. REMINDER OF THE CONCLUSIONS OF PREVIOUS ASSESSMENTS

Opinion on inclusion of 5 December 2007

AB: The actual benefit of this proprietary medicinal product is substantial.

IAB: INCRELEX provides a moderate improvement in actual benefit (IAB III) in the
management of children and adolescents (age 2 to 16 years) with growth failure due to a
severe primary IGF-1 deficiency (primary IGFD).

4.

ANALYSIS OF AVAILABLE DATA

In its opinion of 5 December 2007, the Committee stated that it wished to reassess this
proprietary medicinal product every year in the light of the new data available. Data were first
deposited in September 2009; the new data provided by the company were too fragmentary
to allow this proprietary medicinal product to be reassessed. The company was then asked
to submit all the data available.


4.1. Reminder of the data available on inclusion (5 December 2007)
“The efficacy and safety data for INCRELEX, in the treatment of growth failure in children
and adolescents with primary IGFD, are taken from a double-blind study (F0375g), three
open studies (F0206s, F0671g and F0632g) and a follow-up study (1419)
.

The results of these studies show that there is an improvement in the annual growth rate.
The relevance of these results is difficult to assess in view of the “open nature of three of
these studies, the small number of patients included and a size of effect which differs from
one study to another.


The open-label follow-up study in 75 patients (treated with doses of 100 to 120g/kg 2x/day)
most of whom were included in the earlier studies shows a mean growth rate of 8 cm/year
after the first year of treatment and 5 cm/year during years 2 to 8. This study is still in
progress. Interim results observed after 8 years of treatment are available for only 14

3/20

patients. The impact of INCRELEX on the height reached in adulthood is known for only six
patients (164.4 cm, 150.2 cm, 112 cm, 142 cm, 121.2 cm and 120.8 cm).

In these studies, the patients had, before treatment, a slow growth rate (rate of -3.3 SD ± 1.7)
and a mean height of -6.7 ± SDS, with a failure more severe than that defined by the 1.8
indications of the marketing authorisation (height < -3SD).

The main adverse effects are hypoglycaemia (47%), injection site hypertrophy (32%),
tonsillar hypertrophy (16%) and ear and labyrinth disorders. In the absence of any sound
data on the potential development of anti-IGF-1 antibodies, there is still some doubt about
the longer-term maintenance of efficacy.

4.2. Analysis of the new data available
4.2.1. Study 1419 (see Table 1 in the appendix)
This follow-up study is still in progress. Since 2007, 16 new treatment-naïve patients have
been included, taking the total number of patients included to 91. After an additional two
years of follow-up, the adult height is known for 23 of these 91 patients:
· adult height reached by 13 patients with an IGF-1 deficiency with a variable height The
deficit was: 164.4 cm (SDS -1.5), 152.1 cm (SDS -1.7), 112 cm (SDS -7.8), 124.7 cm
(SDS -6.5), 136.6 cm (SDS -4.1), 137.6 cm (SDS -3.8), 146.4 cm (SDS -4.1), 137.6 cm
(SDS -3.9), 124 cm (SDS -6.7), 153 cm (SDS -2.9), 162.5 cm (SDS -2), 139 cm
(SDS -4.9), 140.9 cm (SDS -4.8).
On inclusion, the mean age of these patients was 6.3 years [2; 15.2] (eight patients
≤two patients 15 years). The mean SDS for the5 years, three patients about 9 years and
height on inclusion was 6.3 cm [-12.1; -3.4].
In these 13 patients the mean adult height reached was 140.8 cm [112; 164.4], i.e. a
mean SDS of -4.2 [-7.8; -1.5] (descriptive analysis).

· The adult height reached by five patients with deletion of the gene coding for GH (outside
Marketing Authorisation) was: 142 cm (SDS -4.8), 121.2 cm (SDS -6.3), 120.8 cm (-6.4),
114.4 cm (SDS -8.5) and 128.8 cm (SDS -5.2).

· adult height Theof five patients who had been treated with another IGF-1 (IGF-1
Pharmacia) before inclusion in study 1419 is not available.

Additional information about the duration of treatment, the initial height in cm and in SDS and
the annual height velocity is given in Table 1 in the appendix.

As regards the other 68/91 patients, 58 left the study before reaching adult height for the
following reasons: poor compliance (n = 4), lost to follow-up (n = 31), poor growth (n = 1),
parental decision (n = 2), impossibi