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Status of long-acting-growth hormone preparations — 2015
YGHIR-01085; No of Pages 6 Growth Hormone & IGF Research xxx (2015) xxx–xxx
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Status of long-acting-growth hormone preparations — 2015 Charlotte Høybye a,b,⁎, Pinchas Cohen c, Andrew R. Hoffman d, Richard Ross e, Beverly M.K. Biller f, Jens Sandahl Christiansen g, for The Growth Hormone Research Society a
Department of endocrinology, metabolism and diabetology, Karolinska University Hospital, Stockholm, Sweden Department of molecular medicine and surgery, Karolinska Institute, Stockholm, Sweden Leonard Davis School of Gerontology, University of Southern California, CA, USA d Department of Medicine, VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, USA e Department of Human Metabolism, University of Sheffield, UK f Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA g Department of Endocrinology, MEA, Aarhus University Hospital, NBG, Aarhus, Denmark b c
a r t i c l e
i n f o
Article history: Received 1 July 2015 Accepted 10 July 2015 Available online xxxx Keywords: Growth hormone Growth hormone deficiency Growth hormone treatment Long-acting growth hormone preparations
a b s t r a c t Growth hormone (GH) treatment has been an established therapy for GH deficiency (GHD) in children and adults for more than three decades. Numerous studies have shown that GH treatment improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life and that the treatment has few side effects. Initially GH was given as intramuscular injections three times per week, but daily subcutaneous injections were shown to be more effective and less inconvenient and the daily administration has been used since its introduction in the 1980s. However, despite ongoing improvements in injection device design, daily subcutaneous injections remain inconvenient, painful and distressing for many patients, leading to noncompliance, reduced efficacy and increased health care costs. To address these issues a variety of long-acting formulations of GH have been developed. In this review we present the current status of long-acting GH preparations and discuss the specific issues related to their development. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Only human growth hormone (GH) exerts metabolic activity in man, and it was not until its isolation from human cadaveric pituitary glands by Raben and its subsequent purification in the late fifties that clinical use of the hormone became possible [1]. Since 1960, treatment of short stature in hypopituitary children has been an accepted therapy, although its use for many years was restricted to three-times weekly dosing and to the shortest children because of the limited availability of the hormone. Since the 1980s, the availability of recombinant GH has enabled larger scale use of GH therapy on a daily basis in children and has extended its use to adults with GH deficiency (GHD). Intramuscular injections three times per week were un-physiological and inconvenient. Careful pharmacological studies showed that daily subcutaneous injections were more effective and less inconvenient for the children, and this daily format was introduced as a routine treatment regimen during the 1980s [2]. GH has a plasma half-life of 3.4 h after subcutaneous injection and ~ 20 min after intravenous injection [3]. The pulsatile and very irregular secretion of GH seen in normal people are impossible to ⁎ Corresponding author at: Department of endocrinology, metabolism and diabetology, Karolinska University Hospital, 171 76 Stockholm, Sweden. E-mail address: [email protected] (C. Høybye).
replicate clinically, even when the GH is administered several times each day. In animal models, pulsatile administration of GH results in better growth and greater IGF-I generation than does continuous GH infusion [4,5]. In contrast, studies in GH deficient (GHD) humans have not revealed any biochemical or physiological differences when comparing treatment with daily subcutaneous GH injections to therapy comprised of several injections per day using the same daily total doses [6,7]. Likewise, continuous infusion of GH in adults with GHD has not demonstrated any clinically meaningful differences in metabolic response in circulating markers of glucose-, lipid- and amino acidmetabolism during six months of therapy when compared to daily injections [8]. Thus, a perfect physiological regimen for GH therapy has not been identified and daily subcutaneous GH injections have been preferred as the most practical mode of administration. It is recommended to administer the daily injections in the evening, since this to some extent mimics the normal pattern for GH secretion and also normalizes the excursions of lipid and amino acid metabolites [2]. The clinical significance, however, of this recommendation has never been documented. Despite ongoing improvements in injection device design, daily subcutaneous administration of GH remains inconvenient, painful and distressing for many patients [9], leading to noncompliance, reduced efficacy and increased health care costs. Compliance is a problem in up to 75% of teenagers, and growth velocity is reduced in the children
http://dx.doi.org/10.1016/j.ghir.2015.07.004 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: C. Høybye, et al., Status of long-acting-growth hormone preparations — 2015, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.07.004
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with poor compliance [9–11]. To address this problem, a variety of long-acting formulations of GH have been developed with the hope of achieving comparable efficacy and safety using fewer total injections [12,13] (Table 1). Long-acting formulations of several hormone drugs, including, GnRH, testosterone, medroxyprogesterone and others are commonly used clinically. The aim of this review is to update the current state of long-acting GH formulations.
2. Growth hormone Human growth hormone (GH) is a 191 amino acid protein consisting of several isoforms. The most abundant pituitary form has a molecular weight of 22 kDa. GH is stored and secreted by the somatotrophs in the anterior pituitary gland; secretion is stimulated by ghrelin and hypothalamic GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin in addition to negative feedback by insulin-like growth factor I (IGF-I) [14]. GH is secreted in pulses, most of which occur during sleep; however, the size and the numbers of pulses are influenced by several factors, including age, gender, acute and chronic illnesses, stress, and nutrition [14,15]. The highest levels of GH are reached in puberty. After puberty, GH levels gradually decline with age, but GH pulses are present throughout life. Women have a higher level of baseline GH and more pulses than do men [14]. GH regulates the production of insulin-like growth factor-I (IGF-I), and together, GH and IGF-I promote longitudinal growth and have important metabolic actions throughout life [14–16]. GH induces a rapid and large increase in resting energy expenditure and fat oxidation resulting in increased protein and glucose synthesis [16]. Through its protein anabolic, lipolytic and antinatriuric effects, GH increases muscle mass and bone formation, reduces fat mass and increases total body water [17,18]. GH increases the peripheral conversion of T4 to T3 and cortisol to inactive cortisone [14] and it may increase insulin resistance and lead to hyperinsulinaemia [15,16]. Intracellular GH signaling is mediated by the GH receptor, a type 1 cytokine receptor [14], a single transmembrane receptor found on most cells in the body. The extracellular GH binding domain of the receptor is also found in the circulation where it serves as a GH binding protein (GHBP) [14]. The GH molecule has two receptor binding sites that bind a preformed receptor dimer, creating a conformation change in the receptor and triggering intracellular signaling and receptor internalization [19]. The majority of circulating IGF-I is produced by the liver. While IGF-I can be bound to 6 different binding proteins, IGFBP 1 to 6, which modulate the effects of IGF-I [20], it is primarily bound to IGFBP-3 and to acid labile subunit [6] in a heterotrimeric complex. This large complex does
Table 1 Long-acting growth hormone formulations.
Depot formulations Pegylated formulations
Product
Current status
Nutropin Depot LB03002 PEG-GH PHA-794428 NNC126-0083 ARX201 Jintrolong
No longer available Approved in Europe No longer in development No longer in development No longer in development Marketed in China for childhood GHD Preclinical studies only Preclinical studies only Phase 2 in children, Phase 2 in adults Phase 2 in children, Phase 3 in adults Phase 2 and 3 in adults Phase 2 in children, phase 3 in adults Phase 2 in adults
BBT-031 CP-016 Prodrug formulations ACP-001/TransCon NNC0195-0092 GH fusion protein TV-1106 technology MOD-4023 LAPSrhGH/HM 10560A VRS-317 GX-H9 ALTU-238 Profuse GH
Phase 2 in children, Phase 3 in adults Phase 2 in adults No longer in development Preclinical studies only
not leave the circulation and can be regarded as a reservoir of IGF-I. The receptor for IGF-I is found in all tissues, and like the insulin receptor, it is a tyrosine kinase receptor [20]. It consists of two ligand-binding units and has a double trans-membrane and a cytoplasmic portion. Hybrid insulin/IGF-I receptors are abundant in the liver. The circulating IGF-I level is commonly used as a biomarker for GH activity in humans. While other factors, including hormones, nutrition and state of health can also modulate IGF-I levels, serum total IGF-I is currently the best available biomarker for GH activity. Free IGF-I and bioactive IGF-I are not routinely measured and their clinical utilities still need to be defined. Calculation of the ratio between IGF-I and IGFBP 3 has been used as an indirect measurement of the free fraction of IGF-I.
3. Growth hormone deficiency (GHD) The incidence of adults with childhood and adulthood onset GHD (defined as profound deficiency) has been reported to affect 1 per 100,000 people per year, with an estimated prevalence of 350/million [21], while the incidence in children has been estimated to be about 1 in 4000 [22]. The most common etiology for childhood onset GHD is idiopathic GHD [22], while the most common causes of adult-onset GHD are pituitary adenomas or other sellar or hypothalamic masses [23]. Short stature is a cardinal symptom in children with GHD [22]. GHD in adults is characterized by a number of clinical features including impaired quality of life, reduced physical activity, increased body fat, decreased lean body mass, decreased bone mineral density and an adverse metabolic profile [17,23]. None of these signs and symptoms is specific but in combination with impaired GH release they constitute a well-defined clinical entity [22,23]. The diagnosis of GHD is established according to specific criteria for the maximal GH response to various different stimulation tests, genetic tests, multiple pituitary hormone deficiencies with low IGF-I levels [22,23]. IGF-I is correlated with GH secretion but because of overlap in IGF-I levels in healthy individuals and patients with GHD, IGF-I is not useful for diagnosing GHD except in patients with multiple other pituitary hormone deficiencies and a low IGF-I for age and sex [22,23]. However, IGF-I expressed as age-adjusted standard deviation score (IGF-I-SDS) is routinely used for monitoring GH dosing.
3.1. Treatment with daily GH Indications for GH treatment include GHD in both children and adults, and in children: Prader Willi, Turner's, and Noonan's Syndromes, idiopathic short stature, children born small for gestational age and children with chronic renal insufficiency. In the US, GH is also approved for the use in short-bowel syndrome and AIDS wasting syndrome. The indication for GH replacement in adults is an established diagnosis of profound GHD according to consensus guidelines [18,23]. The primary objective of GH replacement therapy in children with GHD is to normalize linear growth [22]. The aims of GH treatment are to improve body composition, bone density, quality of life and the patient's metabolic profile and thereby presumably reducing the risk of cardiovascular disease. Major contraindications to GH treatment are active cancer and proliferative diabetic retinopathy [22,23]. In children, treatment is dosed by body surface area, while in adults, treatment with GH is usually initiated with a fixed low dose, and gradually titrated to an IGF-I level within the mid to upper part of the normal range for age-matched healthy controls [22,23]. Most side effects are mild and transient and are attenuated by gradual dose increments. Numerous studies have shown that GH replacement improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life, but there are relatively few studies beyond 5 years of treatment.
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4. Long-acting formulations 4.1. Depot GH formulations 4.1.1. Nutropin depot Nutropin Depot, a collaborative project of Genentech and Alkermes, was a long-acting GH formulation that was approved for treatment of GHD children in 1999. GH was released from the surface of a biocompatible, biodegradable, polylactide co-glycolide acid microsphere soon after injection. A single dose of Nutropin Depot 0.25–0.5 mg/kg in adults with GHD increased IGF-I levels within the normal range for 14–17 days. GH was slowly released over 56 days. Erythema and induration (nodules) at the injection-site occurred in nearly all patients but were not perceived as a limiting factor for patient acceptance. Fasting glucose and insulin concentrations rose transiently, but did not reach levels regarded as clinically significant [24]. In an open-label study of 135 adults with GHD, Nutropin Depot had similar effects on reduction of fat mass and increases in lean body mass as daily injections of GH [25]. In prepubertal children, Nutropin Depot in doses from 0.15 mg/kg to 0.75 mg/kg injected every two weeks increased IGF-I levels for 16–20 days [26]. In a study of 56 naïve prepubertal children with GHD using the same dosing schedule, catch-up growth and normal maturation of bone was observed. However, injection-site reactions were frequently seen [27], multiple injections had to be given for the higher doses that children required, and a noticeable subcutaneous lump remained at the injections site for several days. Nutropin Depot was withdrawn from the market in 2004 because of manufacturing issues.
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all further development was terminated in 2009 [35]. The local-site reactions were independent of either PEG-GH dose or IGF-I levels. The mechanism of the lipoatrophy is unknown [13]. 4.2.2. NNC126-0083 NNC126-0083 was a pegylated long-acting recombinant GH for once-weekly sc injection developed by NovoNordisk. NNC126-0083 consists of a 43-kDa PEG residue attached to glutamine 141 of the GH molecule [36]. In a placebo-controlled study of 33 adults with GHD, weekly injections of 0.001–0.08 mg/kg for three consecutive weeks generated a dose related increase in IGF-I. NNC126-0083 was well tolerated, and no lipoatrophy was observed [37]. In 30 children with GHD randomized to a single dose of NNC126-0083 vs daily GH, a rise in IGF-I levels was observed in all NNC126-0083 dose groups; however, a satisfactory once-weekly IGF-I profile was not reached within the NNC126-0083 dose levels administered [38], and further development was stopped. 4.2.3. ARX201 ARX201 was a GH analog pegylated at amino acid 35 where the native tyrosine was substituted with p-acetylphenylalanine. ARX201 was produced by Ambrx. In an initial clinical trial, 22 adult subjects with GHD received weekly injections of the drug, which had a half-life of 89–102 h, for a total of 6 months. IGF-I levels increased into the normal range, and truncal and total body fat mass declined while lean body mass increased. No lipoatrophy was noted and there were no neutralizing antibodies. In a 6 month phase 2 study of 43 young adults with childhood onset GHD ARX201 was shown to be well-tolerated and improved body composition, lipid profile and quality of life [38]. A dose dependent increase in IGF-I was observed [39]. However, PEG-containing vacuoles were discovered in the epithelial cells of the choroid plexus in monkeys treated with ARX201 and development has been discontinued.
4.1.2. LB03002 LB3002 is a sustained-release GH formulation consisting of microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium-chain triglycerides. It was developed for once weekly administration by LG in conjunctions wih BioPartners GmBH [28]. In a study of 9 adults with GHD who received LB03002 weekly for five weeks, GH levels peaked 6–15 h after injection, remained elevated for 24 h and returned to baseline by 72 h. AUC for IGF-I, normalized for GH dose, was similar to daily GH injections [29]. In a double-blind placebo-controlled study of 152 adults with GHD treated weekly for six months with an average LB3002 dose of 0.4 mg/kg, increases in IGF-I were accompanied by a reduction in fat mass and an increase in lean body mass. Injection-site reactions were common in both groups [30]. A 12-month follow-up in these patients showed that the changes in body composition were maintained [31]. In a phase 2 study of 37 prepubertal children, LB03002 given weekly in increasing doses of 0.2, 0.5 or 0.7 mg/kg showed a dose-related increase (normalization) in IGF-I levels [32]. Three years of GH therapy using LB03002 at doses of 0.5 and 0.7 mg/kg/week achieved similar growth as daily injections of GH (0.003 mg/kg/day). Injection-site reactions were seen in three children [33]. The drug has been approved for use in GHD in Europe, but has not been marketed thus far.
4.2.6. CP016 CP016 is a long-acting GH preparation for bimonthly injections developed by Critical Pharma. The formulation consists of pegylated GH which is mixed with supercritical carbon dioxide to prevent degradation of GH. There are no published reports regarding its efficacy or side effects.
4.2. Pegylated formulations
4.3. Prodrug formulations
Polyethylene glycol (PEG) moieties can be added to peptides to increase their biological half-lives, and many pegylated drugs are currently being marketed, included the growth hormone antagonist, pegvisomant. Several companies have constructed pegylated GH molecules in order to make long-lasting preparations. Pegylation results in prolongation of the in vivo mean residence time of GH, probably through slower absorption and by protecting GH from proteolysis [34].
4.3.1. ACP-001/TransCon ACP-001, which is developed by Ascendis Pharma, is a prodrug that releases unmodified GH by undergoing non-enzymatic cleavage solely dependent on physiological pH and temperature. ACP-001 is rapidly absorbed into the circulation, where it acts as a reservoir from which GH is released during a defined period of time. ACP-001 is designed for once-weekly subcutaneous injections. In a phase 1 study, ACP-001 was safe and well tolerated and demonstrated pharmacodynamic effects (IGF-I) at least comparable to daily hGH injections. In a single dose study, 37 adults with GHD were randomized to one of three dose levels of ACP-001 (equivalent to 0.02, 0.04 and 0.08 mg hGH/kg/week) injected weekly, or to daily hGH (0.04 mg/kg/week) for 28 days. All dose levels of ACP-001 were safe and well tolerated. A total of nine
4.2.1. PHA-794428 PHA-794428 (PEG-GH) was a long-acting GH molecule developed by Pfizer that was intended for weekly subcutaneous injections. However, 13 out of 105 adults with GHD who were treated with PEG-GH developed lipoatrophy at the injection site after the first injection and
4.2.4. Jintrolong Jintrolong is a pegylated GH product that is currently marketed in China by GenSci for treatment of pediatric GH deficiency. Jintrolong is administered once weekly at a dose of 0.2 mg/kg. 4.2.5. BBT-031 BBT-031 is a pegylated GH analog developed by Bolder Biotechnology. It has in rodent models of GHD been shown to stimulate bone and body growth. There are no published reports regarding its efficacy or side effects.
Please cite this article as: C. Høybye, et al., Status of long-acting-growth hormone preparations — 2015, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.07.004
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patients experienced injection site reactions, mostly mild erythema. No lipoatrophy at the injection site or treatment emergent antibodies occurred. IGF-I levels increased in a dose-dependent manner and demonstrated a similar response for ACP-001 0.04 mg/kg/week compared to the corresponding dose of daily GH (0.04 mg/kg/week) [40]. In a six month phase 2 study of TransCon in 52 prepubertal children with idiopathic GHD the increase in IGF-I levels was comparable to daily GH injections [41]. The study showed good tolerability and safety [41]. 4.3.2. NNC0195-0092 NNC0195-0092, developed by Novo Nordisk, consists of a single-point mutation in the GH backbone to which a side chain with terminal fatty acid with non-covalent albumin-binding properties has been attached. The construction prolongs the absorption rate after subcutaneous injection and the non-covalent binding to circulating albumin reduces the clearance of the drug. Results from two placebo-controlled, double blind phase 1 studies have shown that NNC0195-0092 was well tolerated [42]. IGF-I levels increased in a dose dependent manner [42]. Antibodies could not be measured and no clinically relevant difference in local tolerability between NNC0195-0092 and placebo occurred [42]. In total, 105 males were enrolled in the trials, which consisted of five cohorts receiving either a single dose (n = 40) and five cohorts receiving four doses (n = 65) of NNC0195-0092 or placebo [42]. In a phase 2 study short-term multiple dosing of NNC0195-0092 administered subcutaneously to adults with GHD was reported to be well-tolerated and without any serious safety issues [43]. Phase 3 studies are ongoing. 4.4. GH fusion protein technology 4.4.1. TV-1106 (Albutropin) TV-1106 is a long-acting GH developed by Teva Pharmaceutical Industries, Ltd. TV-1106 is comprised of human serum albumin (HSA), genetically fused to the N-terminus of GH. TV-1106 is produced using a yeast (Saccharomyces cerevisiae) that is genetically engineered to express the fusion protein. HSA is a carrier protein with no intrinsic enzymatic or immunologic activity but with a long circulating half-life. The fusion of HSA and GH extends circulation of GH and the pharmacologic activity of GH is retained while the duration of action is longer [44]. In healthy males a single subcutaneous administration of TV-1106 increased plasma IGF-I levels for up to 7 days [45]. Seven consecutive, daily subcutaneous injections of GH resulted in an increase in IGF-I equivalent to that induced by a single administration of TV-1106. TV-1106 was well-tolerated. Phase 2 and phase 3 studies are ongoing. 4.4.2. MOD-4023 MOD-4023 is being developed by Opko Health Inc. in conjunction with Pfizer. In MOD-4023 GH is fused to three copies of the carboxyterminal peptide (CTP) of the beta chain of human chorionic gonadotropin. MOD-4023 is developed for once-weekly administration [46]. In a phase 2 study, 39 adults (33 males and 6 females) with GHD were randomized to treatment with MOD-4023 for four weeks in doses equivalent to 30%, 45% or 100% of the patient's cumulative weekly GH dose [47]. MOD-4023 treatment resulted in a dose-dependent IGF-I response and with doses 45–100% of the weekly cumulative dose, IGF-I values comparable to daily GH injections were obtained. MOD-4023 was well tolerated [47]. In a randomized, controlled Phase 2 study, 56 prepubertal, naïve GHD children were randomized to MOD-4023 onceweekly (0.25–0.66 mg/kg per week) or daily GH (34 μg/kg per day) for 12 months [48]. A dose dependent IGF-I response was observed. All cohorts demonstrated 6 month annualized height velocity above 12 cm/year, correlated with the PK/PD profile in those patients. No unexpected adverse events were observed [48]. 4.4.3. LAPSrhGH/HM10560A LAPSrhGH/HM10560A is produced by Hamni Pharma. It is a purified chemical conjugate of GH and HMC001 (constant region of human
immunoglobulin fragment) linked via a non-peptidyl 3.4 kDa PEG linker. The tolerability and extended half-life of HM10560A were shown in phase 1, single ascending dose study in healthy volunteers. The study also showed that the drug was safe and effective [49]. In an ongoing phase 2 study in adults with GHD 24 week treatment with long acting HM10560A was safe, had a good local tolerability and was effective [49]. 4.4.4. VRS-317 VRS-317, designed by Versartis for once monthly injections, is a fusion protein with a molecular mass of 119 kDa produced in Escherichia coli [50]. The pharmacologically active portion is the GH domain (22 kDa), and the pharmacologically inactive domains are long chains of natural hydrophilic amino acids, called XTEN. XTEN is added to the N- and C-termini of GH. XTEN enables extension of the half-life of GH by increasing the hydrodynamic size of GH and delaying receptormediated clearance through a reduction in receptor binding. The reduced rate of clearance significantly prolongs serum residence times of VRS-317, resulting in enhanced ligand time on target and potentially increasing the probability of a successful ligand-receptor interaction [50,51]. In a placebo-controlled randomized single ascending study in 50 adults with GHD, VRS-317 doses of 0.05, 0.10, 0.20, 0.40 and 0.80 mg/kg were administered. The terminal elimination half-life of VRS-317 at the highest dose was 131 h [52]. A dose–response related IGF-I increase was observed. After a single dose of 0.80 mg/kg, serum IGF-I was maintained in the normal range for 3 weeks without overexposure to high IGF-I levels. No instances of lipoatrophy were recorded [52]. Additionally, a six month phase 2 study in pre-pubertal children with GHD has shown a comparable safety and efficacy profile to historical studies of daily GH injections [53]. 4.4.5. GX-H9 GX-H9, co-developed by Handok and Genexine Inc, uses an antibodyfusion technology. GX-H9 is an rhGH fused to hybrid Fc (hyFc). hy Fc is derived from hybridization of non-cytolytic immunoglobulin Fc portions of IgD and IgG4 without any site-directed mutagenesis. While hyFc extends the half-life of the Fc fused drug molecule mainly based on FcRn recycling mechanism, hyFc also minimizes the loss of bioactivity of the drug molecule, as IgD has the highest hinge flexibility among Igs. The junction site of IgD/IgG4 fusion is buried in the unexposed region which prevents the adverse immunogenicity and cleavage by enzymes [54]. A phase 2 study is ongoing. 4.4.6. ALTU-238 ALTU-238 was developed by Altus Pharmaceuticals Inc. Altu-238 was a long-acting, extended release formulation of GH developed using protein crystallization technology for preserving the GH molecule. Phase 1 and 2 studies were complete and a pediatric Phase 2 study was underway (and an adult Phase 3 study under development) when the company declared bankruptcy in November 2009. 4.4.7. Profuse GH Profuse GH is a fusion of GH to GHBP being developed by Asterion Ltd, which provides an intravascular store of inactive GH with the potential for monthly dosing. To date, only preclinical studies have been reported [34,55]. 5. Specific considerations related to the development of long-acting GH preparations At present, the evaluation of the pharmacodynamic response to GH administration is almost exclusively based upon the measurement of circulating IGF-I. Thus, titration of the GH dose for daily sc injections is most often based upon the IGF-I concentration. This applies for adult replacement in particular, but is also accepted practice among many pediatricians [22,23]. It is generally agreed that prolonged supraphysiological concentrations of IGF-I should be avoided [56].
Please cite this article as: C. Høybye, et al., Status of long-acting-growth hormone preparations — 2015, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.07.004
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In the context of using GH preparations with a longer absorption profiles and extended GH activity, biochemical monitoring of GH replacement may need to be different. Daily injections of GH result in a steady increase and an almost constant level of IGF-I with GH simultaneously present in the circulation for much of the time. In contrast, the long-acting GH preparations might have a somewhat different response resulting in an altered balance between circulating GH and IGF-I. Many questions remain to be answered about long-acting GH: Physiology • Is GH pulsatility important for optimal GH replacement? • The serum half-lives of GH and IGF-I differ dramatically, therefore the ratio of GH and IGF-I changes throughout the day. Would the different ratios created by administering long acting GH yield different outcomes? • What are the consequences for intermediary metabolism of having prolonged elevations of IGF-I and GH?
Efficacy • What other monitoring tools besides IGF-I should be used for longacting GH and would metabolic factors play a role? • What are the key outcomes for phase-III trial designs from the regulatory and clinical perspectives? • Will compliance and adherence improve with long-acting GH availability? • How should the efficacy of long-acting GH be measured in children and in adults?
Safety • What should Phase-4 safety surveillance studies include? • Are there theoretical safety concerns with long-acting GH that differ from daily GH due to prolonged expose? If so, would a period of “off” time, with undetectable GH levels mitigate this? Dosing • Should the dose of long-acting GH be titrated based on measurements of IGF-I? If so, should dose titration be based on mean, peak, intermediate, or trough values; or a combination thereof? • What tools are available to help clinicians convert daily dosing to the ideal long-acting dose for patients already well-controlled on daily GH?
Economic issues • What are the cost/pricing considerations for long-acting GH? • What are the health-economics issues (such as work-productivity and cost)?
6. Conclusion GH treatment has been a well-established therapy in adults and children with GHD for more than three decades. Efficacy and side effects of GH have been well-described in numerous publications. Treatment is usually administered for many years in children and may be life-long in adults, making compliance and adherence very important. Several studies have shown that poor compliance results in reduced efficacy; it is possible that a more convenient administration frequency will improve compliance and therefore health outcomes. Treatment with GH is still associated with discomfort for many patients despite careful injection education and advances in delivery devices. Several long-acting GH formulations have therefore been developed utilizing different techniques and with different pharmacodynamic and
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pharmacokinetic profiles. The early published data show that these drugs can produce sustained physiologic IGF-I levels, resulting in growth in children and body composition improvement in adults. Non-inferiority in efficacy over many years and increased compliance remain to be proven. While there is more to be learned, long-acting GH preparations have the potential to become a useful addition to the currently available treatment options. Conflict of interest statement Charlotte Höybye is an investigator for NovoNordisk, Teva, Ascendis, Versatis and Handok-Genexine and has received occasional consulting honaria from Novo Nordisk and Teva. Pinchas Cohen is a consultant for Ascendis, Opko, Teva, Versartis. Andrew R Hoffman is a consultant for Teva, Versartis and Ambrx. Richard Ross is a Director of Asterion Ltd. Beverly MK Biller is an investigator on research grants to Massachusetts General Hospital from OPKO, Novartis and Novo Nordisk and has received occasional consulting honoraria from Novartis, Novo Nordisk, Pfizer and Versartis. Jens Sandahl Christiansen is an investigator and a consultant for NovoNordisk, Teva and Ascendis. References [1] M.S. Raben, Human growth hormone, Rec. Prog. Horm. Res. 15 (1959) 71–105. [2] K.W. Kastrup, J.S. Christiansen, J.K. Andersen, H. Orskov, Increased growth rate following transfer to daily sc administration from three weekly im injections of hGH in growth hormone deficient children, Acta Endocrinol. (Copenh) 104 (1983) 148–152. [3] M. Hermanussen, K. Geiger-Benoit, W.G. Sippell, Catch-up growth following transfer from three times weekly im to daily sc administration of hGH in GH deficient patients, monitored by knemometry, Acta Endocrinol. (Copenh) 109 (2) (1985) 163–168. [4] K.G. Thorngren, L.I. Hansson, Effect of administration frequency of growth hormone on longitudinal bone growth in the hypophysectomized rat, Acta Endocrinol. (Copenh) 84 (1977) 497–502. [5] R.G. Clark, J.O. Jansson, O. Isaksson, I.A.F. Robinson, Intravenous growth hormone (GH): growth responses to patterned infusions in hypophysectomized rats, J. Endocrinol. 104 (1985) 53–61. [6] J.O. Jørgensen, N. Møller, T. Lauritzen, K.G. Alberti, H. Orskov, J.S. Christiansen, Evening versus morning injections of growth hormone (GH) in GH-deficient patients: effects on 24-hour patterns of circulating hormones and metabolites, J. Clin. Endocrinol. Metab. 70 (1990) 207–214. [7] C. Höybye, M. Rudling, Long-term growth hormone (GH) treatment to GH-deficient adults; comparison between one and two daily injections, J. Endocrinol. Investig. 29 (2006) 950–956. [8] T. Laursen, C.H. Gravholt, L. Heickendorff, J. Drustrup, A.M. Kappelgaard, J.O. Jørgensen, J.S. Christiansen, Long-term effects of continuous subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on the insulin-like growth factor system, insulin sensitivity, body composition, and bone and lipoprotein metabolism in GH-deficient adults, J. Clin. Endocrinol. Metab. 86 (2001) 1222–1228. [9] R.G. Rosenfeld, B. Bakker, Compliance and persistence in pediatric and adult patients receiving growth hormone therapy, Endocr. Pract. 14 (2008) 143–154. [10] R.R. Kapoor, S.A. Burke, S.E. Sparrow, I.A. Hughes, D.B. Dunger, K.K. Ong, C.L. Acerini, Monitoring of concordance in growth hormone therapy, Arch. Dis. Child. 93 (2) (2008) 9147–9148. [11] W.S. Cutfield, J.G. Derraik, A.J. Gunn, K. Reid, T. Delany, E. Robinson, P.L. Hofman, Noncompliance with growth hormone treatment in children is common and impairs linear growth, PLoS One 6 (1) (2011) e16223. [12] C. Giavoli, V. Cappiello, S. Porretti, C.L. Ronchi, E. Orsi, P. Beck-Peccoz, M. Arosio, Growth hormone therapy in GH-deficient adults: continuous vs alternate-days treatment, Horm. Metab. Res. 35 (9) (2003) 557–561. [13] P. Cawley, I. Wilkinson, R.J. Ross, Developing long-acting growth hormone formulations, Clin. Endocrinol. 79 (2013) 305–309. [14] A. Giustina, J.D. Veldhuis, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human, Endocr. Rev. 19 (1998) 717–797. [15] J.O. Jørgensen, N. Møller, T. Wolthers, J. Møller, T. Grøfte, N. Vahl, S. Fisker, H. Orskov, J.S. Christiansen, Fuel metabolism in growth hormone-deficient adults, Metabolism 44 (10 Suppl. 4) (1995) 103–107. [16] J.O. Jørgensen, L. Møller, M. Krag, N. Billestrup, J.S. Christiansen, Effects of growth hormone on glucose and fat metabolism in human subjects, Endocrinol. Metab. Clin. N. Am. 36 (1) (2007) 75–87. [17] P.V. Carroll, E.R. Christ, B.A. Bengtsson, L. Carlsson, J.S. Christiansen, D. Clemmons, R. Hintz, K. Ho, Z. Laron, P. Sizonennko, P.H. Sönksen, T. Tanaka, M. Thorner, Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee, J. Clin. Endocrinol. Metab. 83 (1998) 382–395.
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Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Status of long-acting-growth hormone preparations — 2015 Charlotte Høybye a,b,⁎, Pinchas Cohen c, Andrew R. Hoffman d, Richard Ross e, Beverly M.K. Biller f, Jens Sandahl Christiansen g, for The Growth Hormone Research Society a
Department of endocrinology, metabolism and diabetology, Karolinska University Hospital, Stockholm, Sweden Department of molecular medicine and surgery, Karolinska Institute, Stockholm, Sweden Leonard Davis School of Gerontology, University of Southern California, CA, USA d Department of Medicine, VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, USA e Department of Human Metabolism, University of Sheffield, UK f Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA g Department of Endocrinology, MEA, Aarhus University Hospital, NBG, Aarhus, Denmark b c
a r t i c l e
i n f o
Article history: Received 1 July 2015 Accepted 10 July 2015 Available online xxxx Keywords: Growth hormone Growth hormone deficiency Growth hormone treatment Long-acting growth hormone preparations
a b s t r a c t Growth hormone (GH) treatment has been an established therapy for GH deficiency (GHD) in children and adults for more than three decades. Numerous studies have shown that GH treatment improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life and that the treatment has few side effects. Initially GH was given as intramuscular injections three times per week, but daily subcutaneous injections were shown to be more effective and less inconvenient and the daily administration has been used since its introduction in the 1980s. However, despite ongoing improvements in injection device design, daily subcutaneous injections remain inconvenient, painful and distressing for many patients, leading to noncompliance, reduced efficacy and increased health care costs. To address these issues a variety of long-acting formulations of GH have been developed. In this review we present the current status of long-acting GH preparations and discuss the specific issues related to their development. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Only human growth hormone (GH) exerts metabolic activity in man, and it was not until its isolation from human cadaveric pituitary glands by Raben and its subsequent purification in the late fifties that clinical use of the hormone became possible [1]. Since 1960, treatment of short stature in hypopituitary children has been an accepted therapy, although its use for many years was restricted to three-times weekly dosing and to the shortest children because of the limited availability of the hormone. Since the 1980s, the availability of recombinant GH has enabled larger scale use of GH therapy on a daily basis in children and has extended its use to adults with GH deficiency (GHD). Intramuscular injections three times per week were un-physiological and inconvenient. Careful pharmacological studies showed that daily subcutaneous injections were more effective and less inconvenient for the children, and this daily format was introduced as a routine treatment regimen during the 1980s [2]. GH has a plasma half-life of 3.4 h after subcutaneous injection and ~ 20 min after intravenous injection [3]. The pulsatile and very irregular secretion of GH seen in normal people are impossible to ⁎ Corresponding author at: Department of endocrinology, metabolism and diabetology, Karolinska University Hospital, 171 76 Stockholm, Sweden. E-mail address: [email protected] (C. Høybye).
replicate clinically, even when the GH is administered several times each day. In animal models, pulsatile administration of GH results in better growth and greater IGF-I generation than does continuous GH infusion [4,5]. In contrast, studies in GH deficient (GHD) humans have not revealed any biochemical or physiological differences when comparing treatment with daily subcutaneous GH injections to therapy comprised of several injections per day using the same daily total doses [6,7]. Likewise, continuous infusion of GH in adults with GHD has not demonstrated any clinically meaningful differences in metabolic response in circulating markers of glucose-, lipid- and amino acidmetabolism during six months of therapy when compared to daily injections [8]. Thus, a perfect physiological regimen for GH therapy has not been identified and daily subcutaneous GH injections have been preferred as the most practical mode of administration. It is recommended to administer the daily injections in the evening, since this to some extent mimics the normal pattern for GH secretion and also normalizes the excursions of lipid and amino acid metabolites [2]. The clinical significance, however, of this recommendation has never been documented. Despite ongoing improvements in injection device design, daily subcutaneous administration of GH remains inconvenient, painful and distressing for many patients [9], leading to noncompliance, reduced efficacy and increased health care costs. Compliance is a problem in up to 75% of teenagers, and growth velocity is reduced in the children
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Please cite this article as: C. Høybye, et al., Status of long-acting-growth hormone preparations — 2015, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.07.004
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with poor compliance [9–11]. To address this problem, a variety of long-acting formulations of GH have been developed with the hope of achieving comparable efficacy and safety using fewer total injections [12,13] (Table 1). Long-acting formulations of several hormone drugs, including, GnRH, testosterone, medroxyprogesterone and others are commonly used clinically. The aim of this review is to update the current state of long-acting GH formulations.
2. Growth hormone Human growth hormone (GH) is a 191 amino acid protein consisting of several isoforms. The most abundant pituitary form has a molecular weight of 22 kDa. GH is stored and secreted by the somatotrophs in the anterior pituitary gland; secretion is stimulated by ghrelin and hypothalamic GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin in addition to negative feedback by insulin-like growth factor I (IGF-I) [14]. GH is secreted in pulses, most of which occur during sleep; however, the size and the numbers of pulses are influenced by several factors, including age, gender, acute and chronic illnesses, stress, and nutrition [14,15]. The highest levels of GH are reached in puberty. After puberty, GH levels gradually decline with age, but GH pulses are present throughout life. Women have a higher level of baseline GH and more pulses than do men [14]. GH regulates the production of insulin-like growth factor-I (IGF-I), and together, GH and IGF-I promote longitudinal growth and have important metabolic actions throughout life [14–16]. GH induces a rapid and large increase in resting energy expenditure and fat oxidation resulting in increased protein and glucose synthesis [16]. Through its protein anabolic, lipolytic and antinatriuric effects, GH increases muscle mass and bone formation, reduces fat mass and increases total body water [17,18]. GH increases the peripheral conversion of T4 to T3 and cortisol to inactive cortisone [14] and it may increase insulin resistance and lead to hyperinsulinaemia [15,16]. Intracellular GH signaling is mediated by the GH receptor, a type 1 cytokine receptor [14], a single transmembrane receptor found on most cells in the body. The extracellular GH binding domain of the receptor is also found in the circulation where it serves as a GH binding protein (GHBP) [14]. The GH molecule has two receptor binding sites that bind a preformed receptor dimer, creating a conformation change in the receptor and triggering intracellular signaling and receptor internalization [19]. The majority of circulating IGF-I is produced by the liver. While IGF-I can be bound to 6 different binding proteins, IGFBP 1 to 6, which modulate the effects of IGF-I [20], it is primarily bound to IGFBP-3 and to acid labile subunit [6] in a heterotrimeric complex. This large complex does
Table 1 Long-acting growth hormone formulations.
Depot formulations Pegylated formulations
Product
Current status
Nutropin Depot LB03002 PEG-GH PHA-794428 NNC126-0083 ARX201 Jintrolong
No longer available Approved in Europe No longer in development No longer in development No longer in development Marketed in China for childhood GHD Preclinical studies only Preclinical studies only Phase 2 in children, Phase 2 in adults Phase 2 in children, Phase 3 in adults Phase 2 and 3 in adults Phase 2 in children, phase 3 in adults Phase 2 in adults
BBT-031 CP-016 Prodrug formulations ACP-001/TransCon NNC0195-0092 GH fusion protein TV-1106 technology MOD-4023 LAPSrhGH/HM 10560A VRS-317 GX-H9 ALTU-238 Profuse GH
Phase 2 in children, Phase 3 in adults Phase 2 in adults No longer in development Preclinical studies only
not leave the circulation and can be regarded as a reservoir of IGF-I. The receptor for IGF-I is found in all tissues, and like the insulin receptor, it is a tyrosine kinase receptor [20]. It consists of two ligand-binding units and has a double trans-membrane and a cytoplasmic portion. Hybrid insulin/IGF-I receptors are abundant in the liver. The circulating IGF-I level is commonly used as a biomarker for GH activity in humans. While other factors, including hormones, nutrition and state of health can also modulate IGF-I levels, serum total IGF-I is currently the best available biomarker for GH activity. Free IGF-I and bioactive IGF-I are not routinely measured and their clinical utilities still need to be defined. Calculation of the ratio between IGF-I and IGFBP 3 has been used as an indirect measurement of the free fraction of IGF-I.
3. Growth hormone deficiency (GHD) The incidence of adults with childhood and adulthood onset GHD (defined as profound deficiency) has been reported to affect 1 per 100,000 people per year, with an estimated prevalence of 350/million [21], while the incidence in children has been estimated to be about 1 in 4000 [22]. The most common etiology for childhood onset GHD is idiopathic GHD [22], while the most common causes of adult-onset GHD are pituitary adenomas or other sellar or hypothalamic masses [23]. Short stature is a cardinal symptom in children with GHD [22]. GHD in adults is characterized by a number of clinical features including impaired quality of life, reduced physical activity, increased body fat, decreased lean body mass, decreased bone mineral density and an adverse metabolic profile [17,23]. None of these signs and symptoms is specific but in combination with impaired GH release they constitute a well-defined clinical entity [22,23]. The diagnosis of GHD is established according to specific criteria for the maximal GH response to various different stimulation tests, genetic tests, multiple pituitary hormone deficiencies with low IGF-I levels [22,23]. IGF-I is correlated with GH secretion but because of overlap in IGF-I levels in healthy individuals and patients with GHD, IGF-I is not useful for diagnosing GHD except in patients with multiple other pituitary hormone deficiencies and a low IGF-I for age and sex [22,23]. However, IGF-I expressed as age-adjusted standard deviation score (IGF-I-SDS) is routinely used for monitoring GH dosing.
3.1. Treatment with daily GH Indications for GH treatment include GHD in both children and adults, and in children: Prader Willi, Turner's, and Noonan's Syndromes, idiopathic short stature, children born small for gestational age and children with chronic renal insufficiency. In the US, GH is also approved for the use in short-bowel syndrome and AIDS wasting syndrome. The indication for GH replacement in adults is an established diagnosis of profound GHD according to consensus guidelines [18,23]. The primary objective of GH replacement therapy in children with GHD is to normalize linear growth [22]. The aims of GH treatment are to improve body composition, bone density, quality of life and the patient's metabolic profile and thereby presumably reducing the risk of cardiovascular disease. Major contraindications to GH treatment are active cancer and proliferative diabetic retinopathy [22,23]. In children, treatment is dosed by body surface area, while in adults, treatment with GH is usually initiated with a fixed low dose, and gradually titrated to an IGF-I level within the mid to upper part of the normal range for age-matched healthy controls [22,23]. Most side effects are mild and transient and are attenuated by gradual dose increments. Numerous studies have shown that GH replacement improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life, but there are relatively few studies beyond 5 years of treatment.
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4. Long-acting formulations 4.1. Depot GH formulations 4.1.1. Nutropin depot Nutropin Depot, a collaborative project of Genentech and Alkermes, was a long-acting GH formulation that was approved for treatment of GHD children in 1999. GH was released from the surface of a biocompatible, biodegradable, polylactide co-glycolide acid microsphere soon after injection. A single dose of Nutropin Depot 0.25–0.5 mg/kg in adults with GHD increased IGF-I levels within the normal range for 14–17 days. GH was slowly released over 56 days. Erythema and induration (nodules) at the injection-site occurred in nearly all patients but were not perceived as a limiting factor for patient acceptance. Fasting glucose and insulin concentrations rose transiently, but did not reach levels regarded as clinically significant [24]. In an open-label study of 135 adults with GHD, Nutropin Depot had similar effects on reduction of fat mass and increases in lean body mass as daily injections of GH [25]. In prepubertal children, Nutropin Depot in doses from 0.15 mg/kg to 0.75 mg/kg injected every two weeks increased IGF-I levels for 16–20 days [26]. In a study of 56 naïve prepubertal children with GHD using the same dosing schedule, catch-up growth and normal maturation of bone was observed. However, injection-site reactions were frequently seen [27], multiple injections had to be given for the higher doses that children required, and a noticeable subcutaneous lump remained at the injections site for several days. Nutropin Depot was withdrawn from the market in 2004 because of manufacturing issues.
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all further development was terminated in 2009 [35]. The local-site reactions were independent of either PEG-GH dose or IGF-I levels. The mechanism of the lipoatrophy is unknown [13]. 4.2.2. NNC126-0083 NNC126-0083 was a pegylated long-acting recombinant GH for once-weekly sc injection developed by NovoNordisk. NNC126-0083 consists of a 43-kDa PEG residue attached to glutamine 141 of the GH molecule [36]. In a placebo-controlled study of 33 adults with GHD, weekly injections of 0.001–0.08 mg/kg for three consecutive weeks generated a dose related increase in IGF-I. NNC126-0083 was well tolerated, and no lipoatrophy was observed [37]. In 30 children with GHD randomized to a single dose of NNC126-0083 vs daily GH, a rise in IGF-I levels was observed in all NNC126-0083 dose groups; however, a satisfactory once-weekly IGF-I profile was not reached within the NNC126-0083 dose levels administered [38], and further development was stopped. 4.2.3. ARX201 ARX201 was a GH analog pegylated at amino acid 35 where the native tyrosine was substituted with p-acetylphenylalanine. ARX201 was produced by Ambrx. In an initial clinical trial, 22 adult subjects with GHD received weekly injections of the drug, which had a half-life of 89–102 h, for a total of 6 months. IGF-I levels increased into the normal range, and truncal and total body fat mass declined while lean body mass increased. No lipoatrophy was noted and there were no neutralizing antibodies. In a 6 month phase 2 study of 43 young adults with childhood onset GHD ARX201 was shown to be well-tolerated and improved body composition, lipid profile and quality of life [38]. A dose dependent increase in IGF-I was observed [39]. However, PEG-containing vacuoles were discovered in the epithelial cells of the choroid plexus in monkeys treated with ARX201 and development has been discontinued.
4.1.2. LB03002 LB3002 is a sustained-release GH formulation consisting of microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium-chain triglycerides. It was developed for once weekly administration by LG in conjunctions wih BioPartners GmBH [28]. In a study of 9 adults with GHD who received LB03002 weekly for five weeks, GH levels peaked 6–15 h after injection, remained elevated for 24 h and returned to baseline by 72 h. AUC for IGF-I, normalized for GH dose, was similar to daily GH injections [29]. In a double-blind placebo-controlled study of 152 adults with GHD treated weekly for six months with an average LB3002 dose of 0.4 mg/kg, increases in IGF-I were accompanied by a reduction in fat mass and an increase in lean body mass. Injection-site reactions were common in both groups [30]. A 12-month follow-up in these patients showed that the changes in body composition were maintained [31]. In a phase 2 study of 37 prepubertal children, LB03002 given weekly in increasing doses of 0.2, 0.5 or 0.7 mg/kg showed a dose-related increase (normalization) in IGF-I levels [32]. Three years of GH therapy using LB03002 at doses of 0.5 and 0.7 mg/kg/week achieved similar growth as daily injections of GH (0.003 mg/kg/day). Injection-site reactions were seen in three children [33]. The drug has been approved for use in GHD in Europe, but has not been marketed thus far.
4.2.6. CP016 CP016 is a long-acting GH preparation for bimonthly injections developed by Critical Pharma. The formulation consists of pegylated GH which is mixed with supercritical carbon dioxide to prevent degradation of GH. There are no published reports regarding its efficacy or side effects.
4.2. Pegylated formulations
4.3. Prodrug formulations
Polyethylene glycol (PEG) moieties can be added to peptides to increase their biological half-lives, and many pegylated drugs are currently being marketed, included the growth hormone antagonist, pegvisomant. Several companies have constructed pegylated GH molecules in order to make long-lasting preparations. Pegylation results in prolongation of the in vivo mean residence time of GH, probably through slower absorption and by protecting GH from proteolysis [34].
4.3.1. ACP-001/TransCon ACP-001, which is developed by Ascendis Pharma, is a prodrug that releases unmodified GH by undergoing non-enzymatic cleavage solely dependent on physiological pH and temperature. ACP-001 is rapidly absorbed into the circulation, where it acts as a reservoir from which GH is released during a defined period of time. ACP-001 is designed for once-weekly subcutaneous injections. In a phase 1 study, ACP-001 was safe and well tolerated and demonstrated pharmacodynamic effects (IGF-I) at least comparable to daily hGH injections. In a single dose study, 37 adults with GHD were randomized to one of three dose levels of ACP-001 (equivalent to 0.02, 0.04 and 0.08 mg hGH/kg/week) injected weekly, or to daily hGH (0.04 mg/kg/week) for 28 days. All dose levels of ACP-001 were safe and well tolerated. A total of nine
4.2.1. PHA-794428 PHA-794428 (PEG-GH) was a long-acting GH molecule developed by Pfizer that was intended for weekly subcutaneous injections. However, 13 out of 105 adults with GHD who were treated with PEG-GH developed lipoatrophy at the injection site after the first injection and
4.2.4. Jintrolong Jintrolong is a pegylated GH product that is currently marketed in China by GenSci for treatment of pediatric GH deficiency. Jintrolong is administered once weekly at a dose of 0.2 mg/kg. 4.2.5. BBT-031 BBT-031 is a pegylated GH analog developed by Bolder Biotechnology. It has in rodent models of GHD been shown to stimulate bone and body growth. There are no published reports regarding its efficacy or side effects.
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patients experienced injection site reactions, mostly mild erythema. No lipoatrophy at the injection site or treatment emergent antibodies occurred. IGF-I levels increased in a dose-dependent manner and demonstrated a similar response for ACP-001 0.04 mg/kg/week compared to the corresponding dose of daily GH (0.04 mg/kg/week) [40]. In a six month phase 2 study of TransCon in 52 prepubertal children with idiopathic GHD the increase in IGF-I levels was comparable to daily GH injections [41]. The study showed good tolerability and safety [41]. 4.3.2. NNC0195-0092 NNC0195-0092, developed by Novo Nordisk, consists of a single-point mutation in the GH backbone to which a side chain with terminal fatty acid with non-covalent albumin-binding properties has been attached. The construction prolongs the absorption rate after subcutaneous injection and the non-covalent binding to circulating albumin reduces the clearance of the drug. Results from two placebo-controlled, double blind phase 1 studies have shown that NNC0195-0092 was well tolerated [42]. IGF-I levels increased in a dose dependent manner [42]. Antibodies could not be measured and no clinically relevant difference in local tolerability between NNC0195-0092 and placebo occurred [42]. In total, 105 males were enrolled in the trials, which consisted of five cohorts receiving either a single dose (n = 40) and five cohorts receiving four doses (n = 65) of NNC0195-0092 or placebo [42]. In a phase 2 study short-term multiple dosing of NNC0195-0092 administered subcutaneously to adults with GHD was reported to be well-tolerated and without any serious safety issues [43]. Phase 3 studies are ongoing. 4.4. GH fusion protein technology 4.4.1. TV-1106 (Albutropin) TV-1106 is a long-acting GH developed by Teva Pharmaceutical Industries, Ltd. TV-1106 is comprised of human serum albumin (HSA), genetically fused to the N-terminus of GH. TV-1106 is produced using a yeast (Saccharomyces cerevisiae) that is genetically engineered to express the fusion protein. HSA is a carrier protein with no intrinsic enzymatic or immunologic activity but with a long circulating half-life. The fusion of HSA and GH extends circulation of GH and the pharmacologic activity of GH is retained while the duration of action is longer [44]. In healthy males a single subcutaneous administration of TV-1106 increased plasma IGF-I levels for up to 7 days [45]. Seven consecutive, daily subcutaneous injections of GH resulted in an increase in IGF-I equivalent to that induced by a single administration of TV-1106. TV-1106 was well-tolerated. Phase 2 and phase 3 studies are ongoing. 4.4.2. MOD-4023 MOD-4023 is being developed by Opko Health Inc. in conjunction with Pfizer. In MOD-4023 GH is fused to three copies of the carboxyterminal peptide (CTP) of the beta chain of human chorionic gonadotropin. MOD-4023 is developed for once-weekly administration [46]. In a phase 2 study, 39 adults (33 males and 6 females) with GHD were randomized to treatment with MOD-4023 for four weeks in doses equivalent to 30%, 45% or 100% of the patient's cumulative weekly GH dose [47]. MOD-4023 treatment resulted in a dose-dependent IGF-I response and with doses 45–100% of the weekly cumulative dose, IGF-I values comparable to daily GH injections were obtained. MOD-4023 was well tolerated [47]. In a randomized, controlled Phase 2 study, 56 prepubertal, naïve GHD children were randomized to MOD-4023 onceweekly (0.25–0.66 mg/kg per week) or daily GH (34 μg/kg per day) for 12 months [48]. A dose dependent IGF-I response was observed. All cohorts demonstrated 6 month annualized height velocity above 12 cm/year, correlated with the PK/PD profile in those patients. No unexpected adverse events were observed [48]. 4.4.3. LAPSrhGH/HM10560A LAPSrhGH/HM10560A is produced by Hamni Pharma. It is a purified chemical conjugate of GH and HMC001 (constant region of human
immunoglobulin fragment) linked via a non-peptidyl 3.4 kDa PEG linker. The tolerability and extended half-life of HM10560A were shown in phase 1, single ascending dose study in healthy volunteers. The study also showed that the drug was safe and effective [49]. In an ongoing phase 2 study in adults with GHD 24 week treatment with long acting HM10560A was safe, had a good local tolerability and was effective [49]. 4.4.4. VRS-317 VRS-317, designed by Versartis for once monthly injections, is a fusion protein with a molecular mass of 119 kDa produced in Escherichia coli [50]. The pharmacologically active portion is the GH domain (22 kDa), and the pharmacologically inactive domains are long chains of natural hydrophilic amino acids, called XTEN. XTEN is added to the N- and C-termini of GH. XTEN enables extension of the half-life of GH by increasing the hydrodynamic size of GH and delaying receptormediated clearance through a reduction in receptor binding. The reduced rate of clearance significantly prolongs serum residence times of VRS-317, resulting in enhanced ligand time on target and potentially increasing the probability of a successful ligand-receptor interaction [50,51]. In a placebo-controlled randomized single ascending study in 50 adults with GHD, VRS-317 doses of 0.05, 0.10, 0.20, 0.40 and 0.80 mg/kg were administered. The terminal elimination half-life of VRS-317 at the highest dose was 131 h [52]. A dose–response related IGF-I increase was observed. After a single dose of 0.80 mg/kg, serum IGF-I was maintained in the normal range for 3 weeks without overexposure to high IGF-I levels. No instances of lipoatrophy were recorded [52]. Additionally, a six month phase 2 study in pre-pubertal children with GHD has shown a comparable safety and efficacy profile to historical studies of daily GH injections [53]. 4.4.5. GX-H9 GX-H9, co-developed by Handok and Genexine Inc, uses an antibodyfusion technology. GX-H9 is an rhGH fused to hybrid Fc (hyFc). hy Fc is derived from hybridization of non-cytolytic immunoglobulin Fc portions of IgD and IgG4 without any site-directed mutagenesis. While hyFc extends the half-life of the Fc fused drug molecule mainly based on FcRn recycling mechanism, hyFc also minimizes the loss of bioactivity of the drug molecule, as IgD has the highest hinge flexibility among Igs. The junction site of IgD/IgG4 fusion is buried in the unexposed region which prevents the adverse immunogenicity and cleavage by enzymes [54]. A phase 2 study is ongoing. 4.4.6. ALTU-238 ALTU-238 was developed by Altus Pharmaceuticals Inc. Altu-238 was a long-acting, extended release formulation of GH developed using protein crystallization technology for preserving the GH molecule. Phase 1 and 2 studies were complete and a pediatric Phase 2 study was underway (and an adult Phase 3 study under development) when the company declared bankruptcy in November 2009. 4.4.7. Profuse GH Profuse GH is a fusion of GH to GHBP being developed by Asterion Ltd, which provides an intravascular store of inactive GH with the potential for monthly dosing. To date, only preclinical studies have been reported [34,55]. 5. Specific considerations related to the development of long-acting GH preparations At present, the evaluation of the pharmacodynamic response to GH administration is almost exclusively based upon the measurement of circulating IGF-I. Thus, titration of the GH dose for daily sc injections is most often based upon the IGF-I concentration. This applies for adult replacement in particular, but is also accepted practice among many pediatricians [22,23]. It is generally agreed that prolonged supraphysiological concentrations of IGF-I should be avoided [56].
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In the context of using GH preparations with a longer absorption profiles and extended GH activity, biochemical monitoring of GH replacement may need to be different. Daily injections of GH result in a steady increase and an almost constant level of IGF-I with GH simultaneously present in the circulation for much of the time. In contrast, the long-acting GH preparations might have a somewhat different response resulting in an altered balance between circulating GH and IGF-I. Many questions remain to be answered about long-acting GH: Physiology • Is GH pulsatility important for optimal GH replacement? • The serum half-lives of GH and IGF-I differ dramatically, therefore the ratio of GH and IGF-I changes throughout the day. Would the different ratios created by administering long acting GH yield different outcomes? • What are the consequences for intermediary metabolism of having prolonged elevations of IGF-I and GH?
Efficacy • What other monitoring tools besides IGF-I should be used for longacting GH and would metabolic factors play a role? • What are the key outcomes for phase-III trial designs from the regulatory and clinical perspectives? • Will compliance and adherence improve with long-acting GH availability? • How should the efficacy of long-acting GH be measured in children and in adults?
Safety • What should Phase-4 safety surveillance studies include? • Are there theoretical safety concerns with long-acting GH that differ from daily GH due to prolonged expose? If so, would a period of “off” time, with undetectable GH levels mitigate this? Dosing • Should the dose of long-acting GH be titrated based on measurements of IGF-I? If so, should dose titration be based on mean, peak, intermediate, or trough values; or a combination thereof? • What tools are available to help clinicians convert daily dosing to the ideal long-acting dose for patients already well-controlled on daily GH?
Economic issues • What are the cost/pricing considerations for long-acting GH? • What are the health-economics issues (such as work-productivity and cost)?
6. Conclusion GH treatment has been a well-established therapy in adults and children with GHD for more than three decades. Efficacy and side effects of GH have been well-described in numerous publications. Treatment is usually administered for many years in children and may be life-long in adults, making compliance and adherence very important. Several studies have shown that poor compliance results in reduced efficacy; it is possible that a more convenient administration frequency will improve compliance and therefore health outcomes. Treatment with GH is still associated with discomfort for many patients despite careful injection education and advances in delivery devices. Several long-acting GH formulations have therefore been developed utilizing different techniques and with different pharmacodynamic and
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pharmacokinetic profiles. The early published data show that these drugs can produce sustained physiologic IGF-I levels, resulting in growth in children and body composition improvement in adults. Non-inferiority in efficacy over many years and increased compliance remain to be proven. While there is more to be learned, long-acting GH preparations have the potential to become a useful addition to the currently available treatment options. Conflict of interest statement Charlotte Höybye is an investigator for NovoNordisk, Teva, Ascendis, Versatis and Handok-Genexine and has received occasional consulting honaria from Novo Nordisk and Teva. Pinchas Cohen is a consultant for Ascendis, Opko, Teva, Versartis. Andrew R Hoffman is a consultant for Teva, Versartis and Ambrx. Richard Ross is a Director of Asterion Ltd. Beverly MK Biller is an investigator on research grants to Massachusetts General Hospital from OPKO, Novartis and Novo Nordisk and has received occasional consulting honoraria from Novartis, Novo Nordisk, Pfizer and Versartis. Jens Sandahl Christiansen is an investigator and a consultant for NovoNordisk, Teva and Ascendis. References [1] M.S. Raben, Human growth hormone, Rec. Prog. Horm. Res. 15 (1959) 71–105. [2] K.W. Kastrup, J.S. Christiansen, J.K. Andersen, H. Orskov, Increased growth rate following transfer to daily sc administration from three weekly im injections of hGH in growth hormone deficient children, Acta Endocrinol. (Copenh) 104 (1983) 148–152. [3] M. Hermanussen, K. Geiger-Benoit, W.G. Sippell, Catch-up growth following transfer from three times weekly im to daily sc administration of hGH in GH deficient patients, monitored by knemometry, Acta Endocrinol. (Copenh) 109 (2) (1985) 163–168. [4] K.G. Thorngren, L.I. Hansson, Effect of administration frequency of growth hormone on longitudinal bone growth in the hypophysectomized rat, Acta Endocrinol. (Copenh) 84 (1977) 497–502. [5] R.G. Clark, J.O. Jansson, O. Isaksson, I.A.F. Robinson, Intravenous growth hormone (GH): growth responses to patterned infusions in hypophysectomized rats, J. Endocrinol. 104 (1985) 53–61. [6] J.O. Jørgensen, N. Møller, T. Lauritzen, K.G. Alberti, H. Orskov, J.S. Christiansen, Evening versus morning injections of growth hormone (GH) in GH-deficient patients: effects on 24-hour patterns of circulating hormones and metabolites, J. Clin. Endocrinol. Metab. 70 (1990) 207–214. [7] C. Höybye, M. Rudling, Long-term growth hormone (GH) treatment to GH-deficient adults; comparison between one and two daily injections, J. Endocrinol. Investig. 29 (2006) 950–956. [8] T. Laursen, C.H. Gravholt, L. Heickendorff, J. Drustrup, A.M. Kappelgaard, J.O. Jørgensen, J.S. Christiansen, Long-term effects of continuous subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on the insulin-like growth factor system, insulin sensitivity, body composition, and bone and lipoprotein metabolism in GH-deficient adults, J. Clin. Endocrinol. Metab. 86 (2001) 1222–1228. [9] R.G. Rosenfeld, B. Bakker, Compliance and persistence in pediatric and adult patients receiving growth hormone therapy, Endocr. Pract. 14 (2008) 143–154. [10] R.R. Kapoor, S.A. Burke, S.E. Sparrow, I.A. Hughes, D.B. Dunger, K.K. Ong, C.L. Acerini, Monitoring of concordance in growth hormone therapy, Arch. Dis. Child. 93 (2) (2008) 9147–9148. [11] W.S. Cutfield, J.G. Derraik, A.J. Gunn, K. Reid, T. Delany, E. Robinson, P.L. Hofman, Noncompliance with growth hormone treatment in children is common and impairs linear growth, PLoS One 6 (1) (2011) e16223. [12] C. Giavoli, V. Cappiello, S. Porretti, C.L. Ronchi, E. Orsi, P. Beck-Peccoz, M. Arosio, Growth hormone therapy in GH-deficient adults: continuous vs alternate-days treatment, Horm. Metab. Res. 35 (9) (2003) 557–561. [13] P. Cawley, I. Wilkinson, R.J. Ross, Developing long-acting growth hormone formulations, Clin. Endocrinol. 79 (2013) 305–309. [14] A. Giustina, J.D. Veldhuis, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human, Endocr. Rev. 19 (1998) 717–797. [15] J.O. Jørgensen, N. Møller, T. Wolthers, J. Møller, T. Grøfte, N. Vahl, S. Fisker, H. Orskov, J.S. Christiansen, Fuel metabolism in growth hormone-deficient adults, Metabolism 44 (10 Suppl. 4) (1995) 103–107. [16] J.O. Jørgensen, L. Møller, M. Krag, N. Billestrup, J.S. Christiansen, Effects of growth hormone on glucose and fat metabolism in human subjects, Endocrinol. Metab. Clin. N. Am. 36 (1) (2007) 75–87. [17] P.V. Carroll, E.R. Christ, B.A. Bengtsson, L. Carlsson, J.S. Christiansen, D. Clemmons, R. Hintz, K. Ho, Z. Laron, P. Sizonennko, P.H. Sönksen, T. Tanaka, M. Thorner, Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee, J. Clin. Endocrinol. Metab. 83 (1998) 382–395.
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Please cite this article as: C. Høybye, et al., Status of long-acting-growth hormone preparations — 2015, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.07.004