Development of Long-Acting Growth Hormone Preparations

Michael Scally MD

Doctor of Medicine
10+ Year Member
[Open Access] Christiansen JS, Backeljauw P, Bidlingmaier M, et al. Growth Hormone Research Society Perspective on the Development of Long-Acting Growth Hormone Preparations. European Journal of Endocrinology. Growth Hormone Research Society Perspective on the Development of Long-Acting Growth Hormone Preparations

Objective. The Growth Hormone (GH) Research Society convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting GH preparations (LAGH).

Participants. A closed meeting of 55 international scientists with expertise in growth hormone, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.

Evidence. Current literature was reviewed for gaps in knowledge. Expert opinion was utilized to suggest studies required to address potential safety and efficacy issues.

Consensus Process. Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees re-convened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.

Conclusions. LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.


 
[Open Access] Christiansen JS, Backeljauw P, Bidlingmaier M, et al. Growth Hormone Research Society Perspective on the Development of Long-Acting Growth Hormone Preparations. European Journal of Endocrinology. Growth Hormone Research Society Perspective on the Development of Long-Acting Growth Hormone Preparations

Objective. The Growth Hormone (GH) Research Society convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting GH preparations (LAGH).

Participants. A closed meeting of 55 international scientists with expertise in growth hormone, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.

Evidence. Current literature was reviewed for gaps in knowledge. Expert opinion was utilized to suggest studies required to address potential safety and efficacy issues.

Consensus Process. Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees re-convened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.

Conclusions. LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.
Now we just need China to make a cheap version! lol
 
Strasburger CJ, Vanuga P, Payer J, et al. MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults

OBJECTIVE: Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study's objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once weekly in GHD adults.

DESIGN: 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose.

The study included 2 stages:
Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023.
Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.

RESULTS: Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well-tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.

CONCLUSIONS: Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile, and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
 
[OA] Pharmacokinetics, Pharmacodynamics, and Safety of a Long-Acting Human Growth Hormone (MOD-4023)

Daily injections of growth hormone (GH) as replacement therapy in GH-deficient (GHD) patients may cause poor compliance and inconvenience. C-terminal peptide-modified human GH (MOD-4023) has been developed for once-weekly administration in GHD adults and children.

In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD-4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double-blind, vehicle-controlled, randomized study design.

The study was conducted in 42 healthy Japanese (n = 21) and Caucasian (n = 21) men receiving either MOD-4023 at a dose of 2.5, 7.5, or 15 mg or vehicle. In the 2.5- and 7.5-mg cohorts, no differences in mean MOD-4023 serum concentration were found between Japanese and Caucasian subjects.

A comparison of PK parameters in the 15-mg group suggests a slower absorption rate of MOD-4023 in Japanese subjects. PD analysis showed no apparent differences in IGF-1 and IGFBP-3 plasma concentrations between the Japanese and Caucasian subjects and indicated that a dose of 15 mg achieved the maximal effect in both ethnic groups.

MOD-4023 demonstrated a favorable safety profile and local tolerance following single-dose subcutaneous administration.

This study provides additional support for the development of MOD-4023 as a long-acting human growth hormone formulation for once-weekly administration.

Kramer WG, Jaron-Mendelson M, Koren R, Hershkovitz O, Hart G. Pharmacokinetics, Pharmacodynamics, and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults. Clin Pharmacol Drug Dev. Pharmacokinetics, Pharmacodynamics, and Safety of a Long‐Acting Human Growth Hormone (MOD‐4023) in Healthy Japanese and Caucasian Adults
 
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