Increlex(R) Phase IIIb Study Results Demonstrating Dose-Dependent Height Velocity Increase In Primary IGFD Short Stature Population And Other Increlex

Main Category: Endocrinology
Also Included In: Pediatrics / Children's Health
Article Date: 13 Nov 2008 - 3:00 PDT

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Tercica, Inc., a wholly-owned subsidiary of Ipsen (Euronext: IPN) today announced Phase IIIb clinical trial results demonstrating that Increlex® (mecasermin (rDNA origin) injection) achieved statistically significant dose-dependent first-year height velocity increases in children with Primary IGF-1 Deficiency (Primary IGFD) when administered as a twice-daily injection. A second exploratory study demonstrated that when Increlex® is given as a once-daily regimen in the Primary IGFD population, Increlex® achieved statistically significant dose-dependent first-year height velocity increases. Tercica presented the data from both studies, MS301 and MS308 respectively, along with other data presentations for Increlex® at the 13th International Congress of Endocrinology (ICE) meeting in Rio de Janeiro, Brazil. Increlex® is marketed in the United States and other countries for the treatment of growth failure in children with Severe Primary IGFD using twice-daily injections.

"The results from both the MS301 and the MS308 studies demonstrate the potential for good growth in children beyond the Severe Primary IGFD indication and the need to further explore the potential of Increlex® therapy in children with short stature to improve growth rates," said L. Kurt Midyett, MD, Medical Director, Children's Mercy Hospital and Clinics.

"For children with growth hormone deficiency, growth hormone is the obvious choice to help them achieve normal growth," said Philippe F. Backeljauw, MD, Professor of Pediatrics, Cincinnati Children's Hospital Medical Center. "These results, however, point to the potential that Increlex® may have to improve growth in patients that are insensitive to growth hormone and would need more IGF-1 to achieve normal growth. Further data will be required to better define the contribution IGF-1 may have in the category of growth therapies."

Safety and Efficacy of Twice-Daily rhIGF-1 Treatment in Prepubertal Children with Primary IGF-1 Deficiency: Results from a Randomized Clinical Trial

Tercica gave an oral presentation at the ICE meeting on data from its MS301 study, a 12-month, multi-center, randomized, open-label study, which compared twice-daily Increlex® treatment (80, 120 μg/kg) with observation-only in children with growth failure due to Primary IGFD. Primary IGFD was defined as height and IGF-1 standard deviation scores of <-2, and maximally stimulated serum growth-hormone levels of > 7 ng/mL. The data from the 136-patient study show statistically significant greater first-year growth results for patients receiving twice-daily dosing of Increlex® compared to the untreated control group and a clear dose response. The most commonly observed side effects in this study were headache, vomiting and hypoglycemia.

Dr. George Bright, Vice President and Medical Director, Endocrinology, Tercica, presented this data on November 9 during the Oral Presentation Session "Pediatric endocrinology 1" titled:

- Safety and Efficacy of Twice-Daily rhIGF-1 Treatment in Prepubertal Children with Primary IGF-1 Deficiency: Results from a Randomized Clinical Trial. [OP #007] LK Midyett, A Rogol, J Frane, GM Bright, Children's Mercy Hospital, Kansas City, MO, University of Virginia Charlottesville, VA, Riley Hospital, Indiana University School of Medicine, Indianapolis, IN, Santa Monica, CA, and Tercica, Brisbane, CA

Analysis of Hypoglycemic Events in a Clinical Trial of rhIGF-1 Treatment of Children with Primary IGFD

Tercica also announced the results of an evaluation of the incidence of hypoglycemic events in children with growth failure due to Primary IGFD who were treated with rhIGF-1. These results, from the 12-month, multi-center, open-label clinical trial MS301, compared twice-daily Increlex® treatment (40, 80, 120 μg/kg) with observation-only in children with growth failure due to Primary IGFD. Hypoglycemia and decreased blood glucose were both considered hypoglycemic events for this analysis. In all cases hypoglycemic events were managed by subsequent food intake. The results, from a cohort of 111 patients on active treatment with Increlex® and 25 patients in the untreated observation group, showed that hypoglycemia was not dose-related and occurred in 14% of treated and 8% of untreated subjects. The results demonstrated that hypoglycemia was much less common among children with Primary IGFD during the first year of rhIGF-1 treatment than in previous studies examining Severe Primary IGFD. Similar results to those observed in MS301 were observed in the Increlex® IGFD registry, a naturalistic observational trial in over 500 patients.

The poster describing these results is titled:

- Analysis of Hypoglycemic Events in a Clinical Trial of rhIGF-1 Treatment of Children with Primary IGF-1 Deficiency. [Poster #PO0716] A Rogol, J Frane, and GM Bright, University of Virginia Charlottesville, VA, Riley Hospital, Indiana University School of Medicine, Indianapolis, IN, Santa Monica, CA, and Tercica, Brisbane, CA

Safety and Efficacy of Once-Daily rhIGF-1 Treatment in Prepubertal Children with Primary IGF-1 Deficiency: Results from a Clinical Trial

Tercica communicated data from MS308, an ongoing single-arm, open-label trial assessing once-daily dosing of rhIGF-1 in 45 prepubertal children with Primary IGFD. These results reflect the one year experience of 45 patients enrolled in the MS308 trial and showed that once-daily dosing of Increlex® significantly increased the first-year height velocities in a dose-dependent manner. The effect of the once-daily dosing on first-year height velocities (p < 0.0001) was similar to that observed with twice-daily dosing in MS301. While the evaluation of safety and efficacy is ongoing, the once-daily dosing regimen (up to 240 μg/kg) was found to be generally safe and well tolerated.

The poster describing these data was displayed on November 11 during the Poster Session "Pediatric endocrinology/development" titled:

- Safety and Efficacy of Once-Daily rhIGF-1 Treatment in Prepubertal Children with Primary IGF-1 Deficiency: Results from a Clinical Trial. [Poster #PO0719] GM Bright, D Rogers, L Gonzalez Mendoza, J Frane, Tercica Inc., Brisbane, CA, Cleveland Clinic, Cleveland, OH, Miami, FL, and Santa Monica, CA

Safety and Efficacy of Increlex® Treatment in the IGFD Registry

A second oral presentation was given by Tercica at the ICE meeting on the safety and efficacy of Increlex® based on the IGFD Registry database. Over 500 patients have enrolled in the IGFD Registry since the beginning of the Web-based program in May 2006. The IGFD Registry database allows physicians to register and enter information about their experiences with the use of Increlex® in treating children with short stature and low IGF-1 levels on a real-time basis. The efficacy analysis presented at the meeting was based on the first-year height velocity of 86 pre-pubertal children who were tracked for 1 year. The children were divided into two groups with one group receiving doses of at least 100 μg/kg BID (mean dose per injection 115 μg/kg) and a second group receiving doses below 100 μg/kg BID (mean dose per injection 73 μg/kg). There were no statistically significant differences in the baseline characteristics of the two groups in terms of their initial height, their parents' height or their levels of growth hormone and IGF-1. Higher doses (at least 100 µg/kg BID) were associated with statistically significant better growth rates of 7.7cm/yr vs. 6.8 cm/yr in the lower dose group (below 100 µg/kg BID). The safety data presented are based on 365 patients who were followed for a total of 310 patient-years. The safety analysis found no statistically significant relationship to dose, and so should not affect dose selection. No new safety signals or unexpected serious adverse drug experiences occurred. Incidence of hypoglycemia and headache was 6.8% and 4.7%, respectively.

"The Registry database confirms that children on Increlex® therapy at the higher end of the recommended-dose range (≥ 100 μg/kg BID) achieved better growth rates than children treated with lower doses, and these data demonstrated that adverse events were not dose-related," said Sandra L. Blethen, M.D., Ph.D., Vice President, Medical Affairs at Tercica.

The oral presentation, presented by Dr. Blethen on November 12, is titled:

- Safety and Efficacy of Increlex® Treatment in the IGFD Registry. [OP #083] AJ Cohen, E Estrada, S Blethen, J Kuntze, J Hertz, and J Frane, The Endocrine Clinic, Memphis, TN, University of Connecticut School of Medicine, Hartford, CT, Tercica, Inc., Brisbane, CA, and Santa Monica, CA

Prevalence of Primary IGFD Among Untreated Children with Short Stature in a Prospective, Multi-center Study

Tercica also announced data from a prospective, multi-center study, which showed that Primary IGFD is common among untreated children with short stature who return for follow-up and that for these patients, growth velocities tend to be lowest among children with the lowest IGF-1 levels. "This study further demonstrates the importance of evaluating IGF-1 when assessing patients with growth hormone deficiency and idiopathic short stature and importantly, helps characterize children with short stature and Primary IGFD," said Dr. Bright.

This prospective study, conducted at eight pediatric endocrinology clinics in the United States, characterized data from 202 untreated children with short stature who returned to a pediatric endocrinology clinic for follow-up prior to initiating treatment. Patients were characterized based on their IGF-1 and GH levels, and short stature was defined as a height standard deviation score of <-2 at age 2-16 years. Of the 107 patients with growth hormone stimulation test results who remained untreated at their follow-up visit, 26% of the patients had low IGF-1 levels and normal GH levels (Primary IGFD). Repeated blood sampling of these patients found consistent IGF-1 status results in 88% of the patients.

The poster describing these results is titled:

- Prevalence of Primary IGFD Among Untreated Children with Short Stature in a Prospective, Multi-center Study. [Poster #PO0715] Q Van Meter, LK Midyett, L Deeb, J Frane and GM Bright on behalf of the IGFD Prevalence Study Group, Peachtree City, GA, Pediatrics, Children's Mercy Hospital, Kansas City, MO, Children's Clinic, Tallahassee, FL, Santa Monica, CA, Tercica Inc., Brisbane, CA

About Increlex® (mecasermin (rDNA origin) injection)

The active ingredient of Increlex® is recombinant human insulin-like growth factor-1 (IGF-1). IGF-1 is the direct mediator of growth hormone's (GH) effect on statural growth, and must be present for normal growth of bones and cartilage in children. In Primary IGFD, children's serum IGF-1 levels are low, despite the presence of a normal or elevated GH level. Without adequate IGF-1, children cannot achieve normal height. In children with this disorder, low IGF-1 levels are due to growth-hormone resistance associated with mutations in GH receptors, post-GH receptor signaling pathways, or to defects in IGF-1 gene expression. Some individuals may also have a range of metabolic disorders, including lipid abnormalities, decreased bone density, obesity and insulin resistance.

Increlex® has been marketed in the United States by Tercica since early 2006 for the treatment of children with Severe Primary IGFD. Severe Primary IGFD is defined by height and IGF-1 levels at least three standard deviations below the mean for age and sex, and presence of normal or elevated GH level.

About Ipsen

Ipsen is an innovation-driven international specialty pharmaceutical group with over 20 products on the market and a total worldwide staff of nearly 4,000. Its development strategy is based on a combination of specialty products, which are growth drivers, in targeted therapeutic areas (oncology, endocrinology and neuromuscular disorders), and primary care products which contribute significantly to its research financing. The location of its four Research & Development centres (Paris, Boston, Barcelona, London) and its peptide and protein engineering platform give the Group a competitive edge in gaining access to leading university research teams and highly qualified personnel. More than 700 people in R&D are dedicated to the discovery and development of innovative drugs for patient care. This strategy is also supported by an active policy of partnerships. In 2007, Research and Development expenditure was about €185 million, in excess of 20% of consolidated sales, which amounted to €920.5 million while total revenues amounted to €993.8 million. Ipsen's shares are traded on Segment A of Euronext Paris (stock code: IPN, ISIN code: FR0010259150). Ipsen's shares are eligible to the "Service de Règlement Différé" ("SRD") and the Group is part of the SBF 120 index. For more information on Ipsen, visit our website at http://www.ipsen.com.

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