Journal Club

Ovidiu Galescu MD

24-Month Use of Once-Weekly GH, LB03002, in

Prepubertal Children With GH Deficiency

Vaman Khadilkar, Klavdia A. Radjuk, Elena Bolshova, Rajesh Khadgawat, Mohamed El Kholy, Meena Desai, Valentina Peterkova, Veronica Mericq, Jurgen Kratzsch, E. Christine Siepl, Dieter Martin, Prema Lopez, Hyi-Jeong Ji, Yoon Ju Bae, Jin Hwa Lee, and Paul H. Saenger

Department of Paediatric Endocrinology (V.K.), Jehangir Hospital, Pune 411004, India; Second Children’s Hospital (K.A.R.), Minsk 220020, Belarus; Institute of Endocrinology and Metabolism (E.B.), Academy of Medical Sciences, Kiev 04114, Ukraine; Department of Endocrinology (R.K.), All India Institute of Medial Sciences, New Delhi 110029, India; Department of Pediatrics (M.E.K.), Ain Shams University, Cairo 12311, Egypt; Sir Hurkisondas Nurrotumdas Hospital and Research Centre (M.D.), Mumbai 400004, India; Endocrinological Scientific Center (V.P.), Russian Academy of Medical Sciences, Moscow 117036, Russia; Institute of Maternal and Child Research (V.M.), Santiago de Chile 8389100, Chile; Institute for Laboratory Medicine (J.K.), Leipzig 04103, Germany; Biopartners GmbH (E.C.S., D.M., P.L.), Baar 6340, Switzerland; LG Life Sciences Ltd (H.-J.J., Y.J.B., J.H.L.), Seoul 110-783, South Korea; and Department of Pediatrics (P.H.S.), Winthrop University Hospital, Mineola, New York, USA

Objective

to examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration

Design

phase III, 12-month, multinational, randomized, open-label, comparator controlled trial with a 12-month uncontrolled extension

Intervention:

once-weekly LB03002 or daily GH for 1 year, followed by once-weekly LB03002 for all patients for another year

LB03002 is a once-weekly formulation of recombinant human GH (rhGH) manufactured in genetically modified Saccharomyces cerevisiae and contained in sodium hyaluronate microparticles, which are suspended in medium-chain triglycerides for injection.

Author’s Statement

This is the first report of a global phase III clinical trial of efficacy and safety of a long-acting GH formulation for treatment of GH-deficient children.

Patients and Methods

Eligibility:

• GH treatment-naive and prepubertal(boys >3 and <12 years old; or girls >3 and <11 years old)

• diagnosis of idiopathic or organic GHD,

• height SD score <-2,

• height velocity SDS <-1,

• peak GH concentration <7.0 g/L in two different GH stimulation tests.

Patients and Methods

Exclusion:

• Clinically significant abnormality that affected growth,

• Diabetes mellitus

• Impaired fasting glucose,

• Congenital skeletal abnormalities,

• Poor control/uncontrolled deficiencies of pituitary hormones other than GH.

Patients and Methods

• 31 study centers in the United States, Europe, India, South America, and Egypt;

• 91 patients were randomized to receive LB03002 at a once-weekly dose of 0.5 mg/kg body weight, and

• 89 to receive GHat a daily dose of 0.03 mg/kg (0.21 mg/kg/wk).

• Randomization was stratified by age (7 and 7 years) and gender.

• After the 12-month randomized treatment, patients could choose to continue in a 12-month extension, where children on continued the same regimen and those on daily GH were switched to once-weekly LB03002

Study measurements

• Height - Height SDS - US Centers for Disease Control and Prevention 2000 reference data

• Height velocity - HV SDS was calculated using Swiss reference standards

• Bone age (BA) - Greulich and Pyle

• Predicted adult height - Roche-Wainer-Thissen method

Study measurements

• Serum IGF-1 and IGF binding protein-3 (IGFBP-3)

• In the daily GH-treated group, sample were taken approximately12 hours postdose .

• In the LB03002-treated group, samples were taken on day 4 after the injection,

Study measurements

• Safety, routine blood biochemistry (including fasting glucose) and hematology (including glycated hemoglobin),

• Screening for antibodies against GH and against S. cerevisiae.

• Injection site reactions and local tolerability of LB03002 vs daily GH were rated separately.

• Puberty was evaluated from Tanner staging for pubic hair.

Baseline Demographic and Clinical Characteristics

HV and Changes From Baseline

Height SDS and change from baseline

Results

• No difference between groups in IGF1, IGFBP3 – came within normal ranges

• BA, BA/CA did not differ between groups

• At 24 mo >89% Tanner I

• TEAE : 82.4% in the LB03002 group and 72.4% in the daily GH group

• Administration site AE 47.3% vs 21.8%

Results

GH Antibodies

Thirty-four of 91 patients (37.4%) receiving LB03002 tested positive for GH antibodies at least once during the first year

Second treatment year in 37 of 91 (40.7%) patients being positive for GH antibodies

3.3% in the LB03002 group and 4.6% in the daily GH group tested positive for antibodies to S. cerevisiae at more than one visits

Conclusions

This phase III pivotal trial demonstrated that the growth promoting effect of a once-weekly injection of LB03002 at a dose of 0.5 mg/kg was comparable (noninferior) to that of a standardized daily GH regimen.

Discussion

• Mean HV during the first year was more than 11 cm/y, which represents an expected catch-up growth rate during the first year of GH treatment

• In the second year ,HV was lower, as is anticipated with any GH therapy, yet remained in line with second-year growth rates published for other GH products

Discussion

Post hoc analyses evaluating effects of gender, age, geographical region, and compliance did not disclose any specific pattern related to any of the variables.

When HV SDS was normalized for BA, the difference in second-year growth was no longer statistically significant, suggesting that the difference may possibly relate to differences in BA and bone maturation among individual patients.

Adverse Effects

The adverse event profile of LB03002 was similar to that of daily GH, with the exception of antibody formation and local tolerability

Final Statement• The growth response with once-weekly injection of LB03002

in children with GHD is comparable to that seen with daily GH injections

• IGF-1 increased toward the normal range.

• Growth rates were maintained for 24 months,

• Patients retained a sustained growth potential without excessive bone maturation.

• Switching to LB03002 after 1 year of daily GH resulted in the anticipated growth rate deceleration and maintained the increase in IGF-1.

• LB03002 was well-tolerated, with no unexpected safetyissues.

Thank You !