GHD treatment landscape

Available treatments and guidelines for growth hormone deficiency

The approved treatment for growth hormone deficiency (GHD) is recombinant human growth hormone (rhGH), in its daily long-acting forms.^1,2 In children, the main goal of treatment is to normalise height in childhood and for the child to reach a normal adult height.³ In adults, the main goal of treatment is to improve and reverse the metabolic symptoms of GHD and associated risks.⁴ Treatment with rhGH can have beneficial effects on lipid profile, cardiac performance, body composition and bone mineral density.⁵ This section explores the use of rhGH in routine clinical practice.

Recombinant hGH

Natural GH is produced and secreted in the body by the pituitary gland, while synthetic or daily GH, somatropin, is a therapeutic that mimics naturally occurring hGH. Daily injections of GH have been available for treatment of GHD since 1985 and remain the standard of care.⁶ Daily GH is known to be well tolerated and effective in both children and adults, with large numbers of patients having been assessed in the long-term.^6-11

However, there is variation in the clinical management of GH across the globe, with differing recognition of GHD, availability of GH, and reimbursement.^12,13

Daily GH is indicated for the treatment of children who have growth failure due to GHD and for adults with either childhood or adulthood onset of GHD^14-17

The European Medicines Agency (EMA) recommends that somatropin should not be used in patients showing tumour activity.¹⁸

Guidelines in children

In children, 2016 updates to the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society guidelines (US) recommend an initial dose of 0.16–0.24 mg/kg per week (22–35 μg/kg per day), with individualisation of subsequent dosing.¹⁹ NICE (UK) recommends the choice of daily GH treatment product should be a shared decision between the clinician and the patient and/or their carer.¹⁷ If the following occur, daily GH treatment should be discontinued:¹⁷

• Growth velocity increases less than 50% from baseline in the first year of treatment
• Final height is nearly reached, and growth velocity is less than 2 cm total growth in 1 year
• Impassable problems with adherence
• Final height is attained

Guidelines in adults

The National Institute for Health and Care Excellence (NICE), UK, recommends daily GH treatment if adults meet the following criteria:¹⁶

• Has severe GHD, defined as a peak GH response of less than 9mU/L (3 ng/mL) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test
• Has impaired quality of life (QoL), defined as a reported score of at least 11 on the Quality of life assessment of growth hormone deficiency in adults (QoL-AGHDA) questionnaire; this should be reassessed every 9 months
• Already receiving treatment for any other pituitary hormone deficiencies

Figure 1 indicates some of the common beneficial effects of GH replacement therapy in adults with GHD.

Figure 1. Primary beneficial effects of growth hormone replacement therapy in the treatment of adult growth hormone deficiency (Adapted).²⁰ BMD, bone mineral density; IMT, intima media thickness; LDL, low-density lipoprotein.

Side effects of daily GH treatment are more common in adults than children.²¹ The Endocrine Society Clinical Practice Guideline (US) recommends a starting dose of 0.3 mg/day in patients aged 30–60 years, increasing by 0.1–0.2 mg every 1–2 months.²¹ Because GH secretion decreases with age and older patients are more susceptible to side effects, lower doses are recommended in older patients (>60 years; 0.1–0.2 mg/day) and higher doses in younger patients (<30 years; 0.4–0.5 mg/day).²¹ Women usually require higher doses to reach the same level of insulin-like growth factor (IGF) response.²¹

Treatments for adolescents with growth hormone deficiency

Adolescents who show persistent GHD during the transition period from adolescence to adulthood are recommended to maintain daily GH replacement therapy with the goal of reaching an ideal peak bone mass, satisfactory body composition, lipid and glucose profiles, and an improved QoL.²² The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines recommend daily GH treatment continuation after achievement of final height in this transition period.²³ NICE (UK) recommends that daily GH treatment should be stopped for 2–3 months before a reassessment of GHD status.¹⁶ If GHD is reconfirmed, adult doses can be given.¹⁶ During adolescence, a dose of 0.7 mg/kg per week is recommended by the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society (US).¹⁹

To maximise the window of treatment opportunity in adolescents with GHD, researchers have used gonadotropin-releasing hormone analogues (GnRHa) to suppress or delay puberty, resulting in a larger height gain versus rhGH alone over 3 years of treatment.²⁴ GnRHa has also been widely used in clinical practice.²⁵ However, more research is needed in this area to fully determine the risks and benefits of using GnRHa in adolescents.²⁴

Long-acting growth hormone

Daily rhGH treatment carries a substantial injection burden. To combat this, various formulations of LAGH have been prepared or are in development.^2,6 A weekly injectable LAGH (somatrogon) was first approved in Canada in October 2021, and was EMA approved in February 2022 for the treatment of children and adolescents from 3 years of age.²⁶ The EMA recommended dose is 0.66 mg/kg per week, adjusted by the clinician as necessary.²⁶ Patients weighing over 45 kg requiring doses over 30 mg will be administered the dose in two injections.²⁶ While there have been no LAGH-related adverse events reported in short-term studies, the long-term safety and efficacy of LAGH preparations requires further longitudinal research.^2,6 In addition, LAGH treatments do not mimic the physiology of natural GH secretion.²⁷ Therefore, the daily spontaneous pulsatile secretion patterns of rhGH are not observed with LAGH, unlike daily rhGH.²⁷ Again, long-term data are needed to understand potential metabolic consequences.²⁷

Efficacy and safety of GHD treatments

Efficacy of rhGH in children

Recombinant human growth hormone (rhGH) has been used in clinical practice for more than 30 years.²⁸ It was first approved for the treatment of paediatric GH deficiency (GHD) in 1985 by the FDA, and in 1987 by the European Medicines Agency (EMA).^5,29 A biosimilar of rhGH was first approved for paediatric GHD by the EMA in 2006 and by the FDA in 2007.^28,30

In the long term, daily GH is well tolerated and efficacious in children^7,9,10

The Kabi/Pfizer International Growth Database (KIGS) study is a large international database (N = 83,803) of children treated with rhGH in the real-world.³¹ The baseline median height SDS was –2.99 (–4.44 to –2.06) in boys with idiopathic GHD (IGHD; n = 2,057), and –3.62 (–5.41 to –2.46) in girls with IGHD (n = 1,186).³¹ Following treatment, the near adult height (NAH) was –1.16 (–2.67 to 0.13) in boys and –1.47 (–3.07 to 0.07) in girls.³¹

Safety of rhGH in children

The safety of rhGH in children has been extensively investigated in many studies, driven in part by concerns around a theoretical increased risk for neoplasms.^5,32 Reported adverse events include limb pain, myalgias, arthragias, peripheral oedema, injection site pain, and injection site reaction.⁵ Rare but more serious adverse effects include intracranial hypertension, worsening of scoliosis, slipped capital femoral epiphysis, obstructive sleep apnoea, and pancreatitis.⁵

The SAGhE study assessed mortality in the long-term in 24,232 patients from eight European countries who were treated with rhGH in childhood since its introduction and irrespective of treatment duration.³³ It showed that receiving treatment during childhood is unlikely to be associated with all-cause mortality, but that mortality was instead most likely associated with the underlying diagnosis.³³ In people with isolated GHD, there was no association with increased all-cause mortality and the mean daily or cumulative dose of rhGH.³³ In addition, they had no increase in the risk of mortality from neoplasms.³³ The authors recommend long-term surveillance to ensure detection of potential risks in later life.³³

Although daily rhGH therapy is not associated with cancer mortality or cancer incidence, it may increase the risk of a second tumour in children previously treated for cancer.³⁴ A systematic review and meta-analysis showed significant increases in overall cancer standardised mortality ratios (SMR) (2.74; 95% CI, 1.18–5.41) and the relative risk of neoplasms (1.99; 95% CI, 1.28–3.08; p = 0.002).³⁵

Efficacy of long-acting growth hormone in children

Long-acting growth hormone (LAGH) in children has comparable efficacy to daily rhGH, with no major safety issues in phase 3 clinical trials and a meta-analysis.^27,36 A systematic review and meta-analysis of rhGH treatment in children found that there was no significant difference between high-dose LAGH and daily rhGH when assessing height velocity.³⁶

In a phase 3 study investigating the efficacy and safety over 12 months of weekly somatrogon (an LAGH) versus daily somatropin in children with GHD, weekly somatrogon was noninferior to daily somatropin.³⁷

Safety of long-acting growth hormone in children

In the same phase 3 study, both somatrogon and somatropin were well tolerated, with mild–moderate TEAEs reported by 78.9% of patients in the somatrogon group and 79.1% in the somatropin group.³⁷ However, clinical trials of LAGH have not included children under the age of 2.5 years.³⁸

Some studies suggest there may be additional safety concerns associated with LAGH, including the formation of neutralising anti-drug antibodies, which have the potential to decrease treatment response.³⁸ Therefore, there is a requirement for accurate and reliable anti-drug antibody assays for LAGH treatments.³⁸

In infants and young children with hypoglycaemia associated with severe GHD, LAGH use may create unnecessary risk.³⁸

IGF-1 serum profile levels increase with LAGH treatment.²⁷ While high levels of circulating IGF-1 have been associated with an increased cancer risk, there is no evidence of such associated risks with only transient IGF-1 elevations.²⁷ Long-term data will be needed to understand this potential relationship.²⁷

Maintaining IGF-1 levels within the normal range should be a goal in both LAGH and daily GH treatment²⁷

Epidemiological studies have discussed potential long-term effects of GH, such as induction of neoplasm or development of diabetes.⁴ However, for the weekly injectable LAGH, there is no long-term data on its physiological, metabolic, cardiovascular or carcinogenic effects.²⁷

Safety of rhGH in adults

An international European post-marketing surveillance study evaluated the safety and effectiveness of a biosimilar daily GH in adults with GHD, using data from the PATRO Adults study.⁸ Treatment-related adverse events (TEAEs) were reported in 8.1% of the 1,447 patients in the study.⁸ The most common TEAEs were aching or pain in joints (n = 19), muscle pain (n = 16), headache (n = 14) and peripheral oedema (n = 10).⁸ Mean insulin-like growth factor I standard deviation score (IGF-I SDS) increased from −2.34 at baseline to −0.23 at 12 months and was relatively stable for up to 3 years (Figure 2).⁸ Body mass index was consistent between baseline and 3 years.⁸

Figure 2. Insulin-like growth factor standard deviation score (IGF-I SDS) over time in daily GH-naïve patients (effectiveness population: a subset of the safety set consisting of all patients with a documented baseline visit) (Adapted).⁸ The grey shaded area represents the IGF-I target range. IGF-I, insulin-like growth factor I; SDS, standard deviation score.

An observational, long-term study of 1,293 adults with GHD showed that a somatropin biosimilar did not increase risk of glucose metabolism disorders or of malignancy.^39,40 An increased risk of new malignancies in patients who previously had cancer, however, cannot be excluded.⁴⁰ Guidelines from the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) state that daily GH therapy in patients with a history of active malignancy is contraindicated.²³ Although there are no data suggesting daily GH increases cancer risk in patients with no malignancy history, it is recommended that long-term monitoring and standard cancer screening should take place in patients on daily GH therapy.²³

Risks and benefits of GHD treatment in adults

Table 1 presents a summary of the risks and benefits of growth hormone replacement therapy in adults.

Table 1. Long-term benefits and risks of growth hormone replacement therapy in adult patients with growth hormone deficiency (Adapted).⁴ BMI, body mass index; chol, cholesterol; CRP, C-reactive protein; GHD, growth hormone deficiency; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

In order to avoid potential side effects of GH, dosing is individualised and periodically monitored.⁴ A 2018 review explored risks and benefits of treatment with GH replacement therapy in adults through asking questions about clinical relevance.⁴ Table 2 shows the best available responses to these questions based on the accumulation of study data.⁴

Table 2. Questions and answers about growth hormone replacement therapy in adults with growth hormone deficiency (Adapted).^4,27,36,38 This information is a high-level summary. For full details, please refer to the source literature cited. These are findings of a systematic review and meta-analysis investigating efficacy and safety in children. GH, growth hormone; GHRT, growth hormone replacement therapy; IGF-1, insulin-like growth factor 1; LAGH, long-acting growth hormone; QoL, quality of life.

Treatment adherence and quality of life

Burden of treatment, patient experience, safety and efficacy should be considered when choosing treatments for growth hormone deficiency (GHD). Patient adherence can be an issue for GHD treatment due to forgetfulness, pain/discomfort or being away from home.^35,41 Lower adherence is particularly observed in female and African–American patients.⁴¹ Adherence is multifactorial, and can be affected by various factors in different countries, for example availability and access to treatments.³⁸

Improving adherence could improve outcomes for patients, lower healthcare costs and bring significant benefits to patients.⁴¹ To target the burden of treatment use and improve patient adherence, progress has been achieved in developing a long-acting form of GH.^2,6

A study investigating a once-weekly injectable (somatrogon) versus a once-daily injectable (somatropin) in 87 paediatric patients found that the once-weekly had a lower treatment burden, as measured by the Dyad Clinical Outcome Assessment (DCOA), than somatropin over 12 weeks.⁴²

Although long-acting growth hormone (LAGH) provides convenience and another treatment option for patients, long-term safety and efficacy have not been shown; no studies have evaluated the association between treatment adherence and quality of life (QoL) in either daily GH or LAGH⁴³

With more treatment options for patients with GHD now available, the risk-benefit profile, such as serious treatment-emergent adverse events (TEAEs) and patient QoL, of available options needs to be carefully assessed in the treatment decision process.⁴³

Health economics

The cost effectiveness of somatropin for the treatment of growth hormone deficiency (GHD) in children in the US is estimated to be approximately US$8,900 for each normal height year gained and US$37,000 per quality-adjusted life-year gained; it is therefore suggested that the use of somatropin is reasonable value for money.⁴⁴ A systematic review from 2010 suggests that daily GH treatment for children with GHD, as well as other conditions such as Turner’s syndrome, is cost effective if there is a willingness to pay £20,000–30,000 per quality-adjusted life-year gained.³

It is estimated than a complete multi-annual course of GH treatment costs €100,000⁴⁵

Costs of GHD treatment differ substantially across the globe so the economic burden of GH treatment will vary from country to country.⁴⁵ Although the total cost of GHD treatment is considerable, it can be reduced by improving adherence, reducing wastage and promoting prescriptive appropriateness.⁴⁵

The choice of elements to support treatment, such as the administration device, can affect treatment efficacy and costs to healthcare services.⁴⁶ In a cost-consequence analysis study, administering daily GH in children with an auto-injector that allows for adherence monitoring versus other devices that do not, the auto-injector with daily GH had the lowest financial cost in comparison with other treatments and other devices for administration.⁴⁶