ESPE Abstracts (2014) 82 P-D-1-3-163

ESPE2014 Poster Presentations Growth (2) (13 abstracts)

Six Months Follow-Up Pharmacokinetics and Pharmacodynamics Profile of Once-weekly, CTP-modified Human GH (MOD-4023;): phase 2 Dose Finding Study in Children with GHD Deficiency

Gili Hart a , Zvi Zadik b , Klaudziya Kradziu c , Nataliya Zelinska d , Oleg Malievsky e , Violeta Iotova f , Julia Skorodok g , Ronit Koren a , Leanne Amitzi a & Eyal Fima a

aPROLOR Biotech, Nes Ziona, Israel; bKaplan Medical Center, Rechovot, Israel; c2nd Children City Clinic, Minsk, Belarus; dUkrainian Children Specialized Clinical Hospital, Kyev, Ukraine; eBashkir State Medical University, Ufa, Russia; fUMHAT ‘Sv. Marina’, Varna, Bulgaria; gSt. Petersburg State Pediatric Medical Academy, St Petersburg, Russia

Background: GH replacement therapy currently requires daily injections, which may cause poor compliance, inconvenience and distress for patients. CTP-modified hGH (MOD-4023) is being developed for once-weekly administration in GH deficient (GHD) children. In the present study the longer term pharmacokinetics (PK) and pharmacodynamics (PD) profile of MOD-4023 in GHD naïve children was assessed.

Objective and hypotheses: To assess the long acting properties of MOD-4023 in GHD children.

Method: A randomized, comparator-controlled Phase 2 study in up to 56 pre-pubertal, naïve GHD children receiving three MOD-4023 doses as once-weekly regimen (0.25, 0.48, and 0.66 mg/kg per week) or daily hGH (34 μg/Kg per day) as comparator arm subcutaneously. All patients randomized to receive MOD-4023 doses started treatment for 2 weeks with the low MOD-4023 dose and based on the patient’s dose allocation, followed by a dose increase to the next dose level every 2 weeks until the final allocated dose was reached. MOD-4023, GH, IGF1, and IGFBP3 concentrations were measured monthly on day 3–4 post administration, PK–PD analysis was conducted.

Results: MOD-4023 long acting properties were confirmed in GHD children treated for more than 6 months as compared to daily hGH. MOD-4023 demonstrated extended half-life, increased exposure and reduced clearance. Long term monitoring of pre-dose and trough levels indicated no accumulation of MOD-4023. Following 6 months of MOD-4023 treatment IGF1 SDS increased gradually at a dose proportional manner with no indication for excessive levels. As anticipated, IGFBP3 levels increased reaching the normal range but as anticipated, not at a dose sensitive manner.

Conclusions: MOD-4023 once-weekly injections during the first six months of treatment demonstrated an excellent PK and PD profile supporting once weekly injection in pediatric GHD population and therefore can potentially promote proper growth. In addition, the changes observed in IGF1 and IGFBP3 demonstrate adequate stimulation of the GH–IGF1 axes which were shown to be comparable to that observed with daily hGH treatment.

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