Opko Health Inc (OPK)

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International Journal of Nanomedicine MOD-4023

Post : International Journal of Nanomedicine MOD-4023
URL : http://opkodd.wordpress.com/2014/07/28/international-journal-of-nanomedicine-mod-4023/

July 25 2014

Developments in human growth hormone preparations: sustained-release, prolongedhalf-life, novel injection devices, and alternative delivery routes

* IJN-63507-development-on-human-growth-hormone-preparations--sustained_072514 ( http://opkodd.files.wordpress.com/2014/07/ijn-63507-development-on-human-growth-hormone-preparations-sustained_072514.pdf )

Section 3533#
"A new compound named MOD-4023 fused the carboxy-terminal peptide of human chorionic gonadotropin with rhGH to generate a weekly long-acting rhGH.50 The Phase II study has been accomplished, which suggested its effectiveness and safety in 39 GHD patients. In two cohorts (45% and 100% of each patient’s cumulative weekly rhGH dose) the mean IGF-1 values were comparable to those obtained with daily rhGH at steady state."

MOD-4023
Prolonged half-life/fused with carboxy-terminal peptide

http://opkodd.files.wordpress.com/2014/07/mod4023.jpg&h=192

* Safety and Efficacy Phase 2 Study of Long-acting hGH (MOD-4023) in Growth Hormone Deficient Children ( http://www.clinicaltrials.gov/ct2/show/NCT01592500 )

Once-weekly, CTP-modified hGH (MOD-4023) is effective in growth hormone deficient adults: a phase II, dose and frequency finding study ( http://www.endocrine-abstracts.org/ea/0029/ea0029oc10.5.htm )

Objective: GH replacement therapy currently requires daily injections, which may cause poor compliance and distress for patients. CTP-modified hGH (MOD-4023) is being developed for once-weekly administration in GH Deficient adults and children. The present study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MOD-4023 in GHD adults.

Design and methods: 39 normalized GHDA patients currently treated with daily GH were randomized and switched to 3 dose levels of once-weekly MOD-4023 (30%, 45% or 100% of each patient’s cumulative weekly hGH dose) to evaluate safety and PK/PD profile. The study was comprised of two stages. Stage I included an optimization period and 4 weeks of once-weekly subcutaneously administered MOD-4023. Stage II is an optional 16 week extension period of once weekly MOD-4023 administration to collect further safety information and confirm the results obtained in Stage I. Here we present the results of Stage I.

Results: MOD-4023 was well-tolerated and a dose dependent response of IGF1 concentration was demonstrated. In most patients, IGF1 levels were maintained within ±2 SDS during the 4 weeks, without exceeding +2 SDS at peak levels. In two cohorts (45% and 100%) the mean IGF1 values were comparable to those obtained with daily hGH at steady state. The adverse effects reported were consistent with known hGH related side-effects, and were mostly mild. MOD-4023 was not immunogenic.

Conclusions: Once-weekly, repeated doses of long-acting MOD-4023 were safe and well tolerated in adult GHD patients. IGF1 levels were maintained within the normal range in most MOD-4023 treated patients for the entire 4 weeks of treatment.

Based on the positive results of Stage I, an estimated target dose range for a Phase III study has been established and the 16-week extension study was initiated to further confirm the estimated dose range and to provide additional safety information.

* Strong Data from Lagova™ Phase II Clinical Study Presented during Webcast ( http://investor.opko.com/releasedetail.cfm?ReleaseID=856533 )

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View Presentation ( http://investor.opko.com/common/download/download.cfm?companyid=OPKO&fileid=764088&filekey=d553fff2-dc2c-4f53-a2a8-ec92508dcbf4&filename=Webcast%20ENDO 2014 final 23 6 14_final(3).pdf )  

Pharmacokinetics and Pharmacodynamics Profile of Once-Weekly, CTP-Modified Human Growth Hormone (MOD-4023): Phase 2 Dose Finding Study in Children with Ghd Deficiency ( https://endo.confex.com/endo/2014endo/webprogram/Paper13640.html )

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: MON 0136-0155-Growth and GH: Diagnostic Issues and Treatment
Clinical

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.

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