Pharmacokinetics and Pharmacodynamics Profile of Once-Weekly, CTP-Modified Human Growth Hormone (MOD-4023): Phase 2 Dose Finding Study in Children with Ghd Deficiency

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: MON 0136-0155-Growth and GH: Diagnostic Issues and Treatment
Monday, June 23, 2014: 1:00 PM-3:00 PM
Hall F (McCormick Place West Building)

Poster Board MON-0149
Gili Hart, PhD1, Zvi Zadik2, Klaudziya Radziuk, MD, PhD3, Nataliya Zelinska,, MD, PhD4, Oleg Malievsky, MD, PhD5, Violeta Iotova, Prof. Dr6, Julia Skorodok, MD7, Ronit Koren, Dr8, Leanne Amitzi, MSc9 and Eyal Fima, PhD1
1Prolor Biotech, Nes Ziona, Israel, 2Kaplan Medical Center, Rehovot, Israel, 32nd Children City Clinic, Minsk, Belarus, 4Ukrainian Children Specialized Clinical Hospital, Kyev, Ukraine, 5Bashkir State Medical University, Ufa, Russia, 6UMHAT "Sv. Marina", Varna, Bulgaria, 7St. Petersburg State Pediatric Medical Academy, St. Petersburg, Russia, 8PROLOR, nES ZIONA, Israel, 9PROLOR BIOTECH, Israel
Objective: Growth Hormone (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 Growth Hormone Deficient (GHD) adults and children. In the present study the pharmacokinetics (PK) and pharmacodynamics (PD) profile of MOD-4023 in GHD naïve children was assessed.

Design and methods:  A randomized, comparator-controlled Phase 2 study was conducted in up to 56 pre-pubertal, naïve GHD children receiving one of three MOD-4023 doses as once-weekly regimen (0.25, 0.48, 0.66mg/Kg per week) or daily hGH (34µg/Kg/day) as comparator arm in subcutaneous injections. In order to introduce naïve patients to the allocated MOD-4023 dose in a gradual manner, a stepwise dose increase approach was implemented. All patients randomized to receive one of the three 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 two weeks until the final allocated dose was reached. Subsequently to the second dose administration of the targeted dose MOD-4023, GH, IGF-1 and IGF-BP3 concentrations were measured and PK-PD analysis was conducted utilizing a population based approach.


Results: MOD-4023 administration to GHD children further confirmed its long acting properties and superior properties compared to daily hGH as reflected by extended half-life, increased exposure and reduced clearance. In addition, MOD-4023 Cmax, and AUC were increased at a clear dose proportional manner, while pre-dose and trough levels indicated no accumulation of circulating MOD-4023. IGF-1 and IGF-1 SDS following MOD-4023 administration also increased at a dose proportional manner with no indication for excessive levels at the higher doses and were shown to be normalized and maintained within the normal range up to 168 hrs. As anticipated, IGF-BP3 levels increased reaching the normal range but as anticipated, not at a dose sensitive manner.

Conclusions: MOD-4023 once-weekly treatment at three different doses 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 IGF-1 and IGF-BP3 demonstrate adequate stimulation of the GH-IGF-1 axes which were shown to be comparable to that observed with daily hGH treatment.

Nothing to Disclose: GH, ZZ, KR, NZ, OM, VI, JS, RK, LA, EF

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