A long-acting human growth hormone with delayed clearance (VRS-317): results of a double-blind, placebo-controlled, single ascending dose study in growth hormone-deficient adults

Kevin C J Yuen, Gerard S Conway, Vera Popovic, George R Merriam, Timothy Bailey, Amir H Hamrahian, Beverly M K Biller, Mark Kipnes, Jerome A Moore, Eric Humphriss, George M Bright, Jeffrey L Cleland, Kevin C J Yuen, Gerard S Conway, Vera Popovic, George R Merriam, Timothy Bailey, Amir H Hamrahian, Beverly M K Biller, Mark Kipnes, Jerome A Moore, Eric Humphriss, George M Bright, Jeffrey L Cleland

Abstract

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes.

Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317.

Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study.

Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo).

Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe.

Main outcome measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed.

Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3-5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed.

Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

Trial registration: ClinicalTrials.gov NCT01359488.

Figures

Figure 1.
Figure 1.
Time course of mean VRS-317 concentrations in adult subjects with GHD receiving a single sc dose on day 1. Subjects received a single sc dose of either 0.05 (▴), 0.10 (■), 0.20 (□), 0.40 (●) or 0.80 (○) mg/kg VRS-317.
Figure 2.
Figure 2.
A, Mean change in IGF-1 SDS for placebo and 5 VRS-317 dosing groups. Data represent the mean of subjects in a dose group for the differences for each subject between his or her baseline and each subsequent time point and are not the absolute mean IGF-1 SDS at each time point. Subjects received a single sc dose of either placebo (10 subjects, ×) or 0.05 (8 subjects, ▴), 0.10 (8 subjects, ■), 0.20 (8 subjects, □), 0.40 (8 subjects, ●), or 0.80 (7 subjects, ○) mg/kg VRS-317. B, Extent of normalization of IGF-I SDS after a single sc dose administration of VRS-317. Mean IGF-I SDS for subjects with a baseline IGF-I SDS of ≤ −1.5. Subjects received a single sc dose of either 0.05 (7 subjects, ▴), 0.10 (8 subjects, ■), 0.20 (7 subjects, □), 0.40 (7 subjects, ●), or 0.80 (5 subjects, ○) mg/kg VRS-317.

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