Another sustained-release growth hormone in the pipeline: VRS-317

Human growth hormone molecule

We recently wrote about the sustained-release growth hormone LB03002, which will probably appear on the market fairly soon. This isn’t the only sustained-release growth hormone in the pharmaceuticals pipeline. The American company Versartis [versatis.com] recently published the results of the first human trial with VRS-317, a growth hormone analogue that only requires one injection a month.

We recently wrote about the sustained-release growth hormone LB03002, which will probably appear on the market fairly soon. This isn’t the only sustained-release growth hormone in the pharmaceuticals pipeline. The American company Versartis [versatis.com] recently published the results of the first human trial with VRS-317, a growth hormone analogue that only requires one injection a month.

Growth hormone has a short half-life [the time it takes for half of the molecules of an administered substance to disappear from the blood vessels]. If you inject in the morning, the half-life is 14 minutes. If you inject in the evening, the half-life is 19 minutes. [J Clin Endocrinol Metab. 1993 Jul;77(1):216-20.]

Biotechnologists at Amunix, an American R&D company, decided about a decade ago that there was room for improvement, so they developed the XTEN technology. This involves attaching amino acid chains in the bacteria produced by growth hormone at the extremities of the growth hormone molecule. These amino acid chains a) reduce breakdown by enzymes, b) make the molecule soluble in water and c) prevent immune cells from attacking and destroying the chain. [Nat Biotechnol. 2009 Dec;27(12):1186-90.]

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Once Amunix had refined the XTEN technology it embarked on a joint venture with the pharmaceutical company Versartis. [vertartis.com June 2, 2009] Versartis performed animal studies with VRS-317, the XTEN-version of growth hormone, and discovered that the weight increase was even bigger than that caused by regular growth hormone. [J Pharm Sci. 2012 Aug;101(8):2744-54.]

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Versartis decided it was time for a registered phase-1 trial [NCT01359488]. The results of this trial were recently published in the Journal of Clinical Endocrinology and Metabolism. [J Clin Endocrinol Metab. 2013 Jun;98(6):2595-603.]

The two figures below come from the article. They show the effect of a single subcutaneous injection of different doses of VRS-317 on the levels of VRS-317 and IGF-1 in the blood over the course of one month.

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The researchers discovered that ten percent of the users developed antibodies against growth hormone. They intend to investigate whether this has consequences, but believe that this will not be the case. As far as they can tell from the study they’ve already done VRS-317 is safe.

It is possible however that VRS-317 has other biological effects than those of regular growth hormone. The XTN technology reduces the ‘fit’ of the molecule in the growth hormone receptor. This may reduce the fat-reducing properties of VRS-317 in comparison with those of regular growth hormone.

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.

Yuen KC, Conway GS, Popovic V, Merriam GR, Bailey T, Hamrahian AH, Biller BM, Kipnes M, Moore JA, Humphriss E, Bright GM, Cleland JL.

Source

Endocrinology, Diabetes and Clinical Nutrition, Oregon Health and Science University, Portland, Oregon 97239, USA.

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 ?g/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.

PMID: 23585663 [PubMed – indexed for MEDLINE] PMCID: PMC3667252

Source: http://www.ncbi.nlm.nih.gov/pubmed/23585663

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