Drug Database: Somatropin

Pharmacology

Pharmacology

Mechanism of Action:

Immune modulator. Somatropin, a recombinant human growth hormone (rhGH), is 191 amino acid residues long and is practically identical to human growth hormone (GH) produced by the pituitary gland.^2,5 Somatropin is FDA-approved (under different brand names) for various indications, though it is primarily used for the treatment of growth disorders in children and growth hormone deficiency in adults.^3,6,7 In individuals with HIV, somatropin is FDA-approved to treat HIV-associated wasting or cachexia and may be used off-label to treat HIV-associated lipodystrophy.^5,8

In the body, GH binds to GH receptors located in cell membranes of various tissues, primarily the liver, and consequently promotes the production of insulin-like growth factors (IGF-1 and IGF-2). Growth hormone and IGF-1 and -2 have widespread actions throughout the body and not only facilitate somatic growth, but also effect glucose homeostasis and carbohydrate and lipid metabolism. Growth hormone is also important for immune cell development and function and is necessary for thymic T cell development.^2,9-12

During HIV infection, incomplete immune restoration following treatment with ART may be partly due to limited de novo thymic production of naive CD4 cells.^2,13 Researchers have thus explored whether growth hormone treatment may promote immune restoration in individuals with chronic HIV infection. Previous clinical trials have demonstrated that somatropin administered with ART may have numerous beneficial effects on the immune system, including 1) enhancing thymic size and function, 2) increasing total and naive CD4 cells, 3) restoring HIV-specific T cell and antibody responses, 4) reducing immune activation and cell apoptosis, and 5) improving natural killer (NK) cell function.^2,4,13-15 In a Phase 2 trial (NCT03091374), investigators studied whether somatropin could reduce the size of the latent HIV reservoir in individuals with immune-reconstitution on suppressive ART.⁴

Half-life (T_½):

When administered to individuals with HIV-associated wasting, somatropin 6.0 mg given by subcutaneous (SC) injection and as the brand product Serostim had a half-life of approximately 4.28 ± 2.15 hours. This is similar to the half-life of SC somatropin observed in healthy males without HIV.⁵

Metabolism/Elimination:

Somatropin is metabolized by the kidneys and, to a lesser extent, the liver. Following cleavage in the kidneys, the peptide and amino acid breakdown products reenter systemic circulation.⁵

Select Clinical Trials

Select Clinical Trials

Study Identifiers: ACTG A5198s; ACTG A5174; NCT00050921

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: Not available
Status: This study has been completed.
Study Purpose: The purpose of this open-label pilot study was to evaluate whether somatropin could increase naive CD4 cell production in individuals with incomplete immune restoration on ART.
Study Population:

• Participants were adults with HIV who had been receiving ART for at least 1 year.
• Participants had HIV RNA <400 copies/mL for at least 6 months before study entry and CD4 counts <350 cells/mm³.^13,16

Selected Study Results: Results published in AIDS Research and Human Retroviruses (2010) showed that somatropin 1.5 mg daily added to ART (Arm A) did not result in a significant change in naive CD4 cell count or percentage from baseline to Week 24, as compared to ART alone (Arm B). The primary endpoint of at least a 10% increase in naive CD4 cell percentage was achieved by only one participant in Arm A. After Week 24, participants in Arm A continued on their current dose of somatropin and participants in Arm B added somatropin 3.0 mg daily. By Week 48, participants in both arms had significant increases from baseline in total and naive CD4 cell counts.¹³

Study Identifiers: CTN 298; NCT03091374

Sponsor: McGill University Health Centre/Research Institute of McGill University Health Centre
Phase: 2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether somatropin can reduce the size of the latent HIV reservoir in individuals with immune-reconstitution on suppressive ART.
Study Population:

• Participants were adults with HIV who had been receiving uninterrupted ART for at least 24 months and had been on a stable regimen during the 12 weeks before study entry.
• Participants had undetectable HIV RNA levels (<50 copies/mL) for at least the 24 months before study entry and had undetectable levels confirmed within 60 days of study entry.
• Participants had CD4 counts ≥350 cells/mm³ within 30 days of study entry.^4,17,18

Selected Study Results: Results presented at CROI 2021 showed that somatropin added to ART resulted in a trend towards a reduction in the size of the replication competent latent HIV reservoir from baseline to Week 48.¹⁷

Study Identifier: NCT00071240

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate whether somatropin could increase thymic size and function and increase the number of naive and total T cells in individuals with persistently low CD4 counts despite virologic suppression on ART.
Study Population:

• Participants were adults with HIV who had been receiving an effective ART regimen for at least 1 year.
• Participants had HIV RNA <1,000 copies/mL for at least 1 year prior to study entry and had CD4 counts <400 cells/mm³ in the past 6 months prior to study entry.^14,19

Selected Study Results: Results published in The Journal of Clinical Investigation (2008) showed that somatropin treatment was associated with an increase in thymic mass. Somatropin treatment also enhanced thymic function as evidenced by increased frequency of TCR rearrangement excision circles (TRECs) in PBMCs and number of circulating naive and total CD4 cells.¹⁴

Study Identifiers: VIHCREC01; NCT00287677

Sponsor: Germans Trias i Pujol Hospital
Phase: 4
Status: This study has been completed.
Study Purpose: The purpose of this open-label pilot study was to evaluate whether thymic restoration mediated by somatropin could restore antigen-specific cellular and humoral immune responses in individuals with severe immunosuppression on ART.
Study Population:

• Participants were adults with HIV who had been on ART for at least 1 year.
• Participants had HIV RNA <50 copies/mL and had CD4 counts >50 cells/mm³.
• Participants lacked antibody and CD4 cell immune responses to vaccination with at least one of three antigens (hepatitis A, hepatitis B, and tetanus toxoid).^15,20

Selected Study Results: Results published in Immunology (2011) showed that thymus reconstitution through treatment with somatropin restored antigen-specific CD4 cell and antibody immune responses in participants with immunosuppression on ART.¹⁵

Other trials have also investigated the immunomodulatory role of somatropin administration during HIV infection, including:

• NCT00119769: A Phase 4 substudy that assessed the effects of low dose somatropin on HIV-specific T cell responses and T cell characteristics in individuals with HIV on effective ART.^2,21
• NCT01130376: A Phase 1 trial that explored the ability of the therapeutic HIV vaccine GTU-MultiHIV B given in combination with cytokine (aldesleukin and sargramostim) plus growth hormone (somatropin) therapy to reduce T cell dysfunction in individuals with clade B HIV on suppressive ART.^22,23

Adverse Events

Adverse Events

ACTG A5174 (NCT00050921):

In this pilot study, 60 participants were randomized equally to two treatment arms. Eight participants discontinued the study because of an adverse event (AE). Carpal tunnel syndrome that was probably related to somatropin treatment was suspected or diagnosed in six participants. In one participant who entered the study with diagnosed anal carcinoma, progression of the disease was possibly related to somatropin. Few Grade 3 or higher AEs and laboratory abnormalities occurred, and they were distributed equally across the study arms.^13,16

CTN 298 (NCT03091374):

In this Phase 2 study, 12 participants initiated therapy with somatropin; however, only three of the 12 participants completed 48 weeks of treatment. The primary reason for study drug discontinuation was musculoskeletal pain, which occurred in six participants.^4,17

NCT00071240:

Twenty-two participants in this Phase 2 trial were randomized equally to either a growth hormone arm or a control arm. Nine participants dropped out of the trial early, including five participants who discontinued somatropin prematurely. In three of the five participants, somatropin was discontinued because of AEs – diabetes in two participants and carpal tunnel syndrome in one participant. The somatropin dose was temporarily withheld or prematurely reduced by at least 50% because of AEs in seven other participants.^14,19

Overall, 95% of participants reported an AE of Grade 2 or higher. The majority of these AEs were known effects of somatropin therapy and included arthralgias, abnormalities in glucose metabolism, edema, and carpal tunnel syndrome. Also noted were three unexpected occurrences of tenosynovitis of the hand and three cases of lymphoma incidentally diagnosed in one screened participant and two enrolled participants. Among the three participants with lymphoma, only one received any somatropin.¹⁴

VIHCREC01 (NCT00287677):

In this Phase 4 study, eight participants were enrolled in Group A (somatropin plus vaccinations), six participants were enrolled in Group B (somatropin only), and eight participants were enrolled in Group C (vaccinations only). Two participants (one each from Groups B and C) withdrew from the trial early. During the study, a dose reduction of somatropin was required for nine participants because of either abnormal levels of IGF-1 or AEs. Specifically, dose reductions were implemented because of increased IGF-1 levels (five cases) or an AE (three cases of arthralgia or myalgia and one case each of peripheral edema and peripheral neuropathy). At least two dose reductions of somatropin were needed in four participants.^15,20

Among participants who received somatropin during the trial, the following AEs were reported: five cases of arthralgia, two cases of hand edema, and one case each of myalgia, peripheral neuropathy, carpal tunnel syndrome, asthenia, and acute respiratory infection. Although AEs were generally mild, somatropin treatment was interrupted because of carpal tunnel syndrome in one participant and hand edema in another participant. One participant was hospitalized because of acute respiratory infection.¹⁵

Additional AEs known to be associated with somatropin are described in the FDA-approved Full Prescribing Information for Serostim.

Drug Interactions

Drug Interactions

Somatropin may affect the clearance of drugs that are metabolized by CYP enzymes; therefore, monitoring is recommended when coadministering somatropin with such compounds.⁵

Additional drug interactions known to be associated with somatropin are described in the FDA-approved Full Prescribing Information for Serostim.

References

References

1. National Center for Biotechnology Information. PubChem Compound Summary for SID 472423450, Somatropin. Accessed August 16, 2023
2. Herasimtschuk AA, Hansen BR, Langkilde A, Moyle GJ, Andersen O, Imami N. Low-dose growth hormone for 40 weeks induces HIV-1-specific T cell responses in patients on effective combination anti-retroviral therapy. Clin Exp Immunol. 2013;173(3):444-453. doi:10.1111/cei.12141. Accessed August 16, 2023
3. DrugBank. Somatotropin. Accessed August 16, 2023
4. McGill University Health Center. A proof-of-concept study to assess the effect of recombinant human growth hormone on the size of the replication-competent viral reservoir in HIV-infected individuals on suppressive antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 21, 2017. NLM Identifier: NCT03091374. Accessed August 16, 2023
5. EMD Serono, Inc. Serostim: full prescribing information, February 2, 2022. DailyMed. Accessed August 16, 2023
6. Reh CS, Geffner ME. Somatotropin in the treatment of growth hormone deficiency and Turner syndrome in pediatric patients: a review. Clin Pharmacol. 2010;2:111-122. Accessed August 16, 2023
7. Cai Y, Xu M, Yuan M, Liu Z, Yuan W. Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes. Int J Nanomedicine. 2014;9:3527-3538. doi:10.2147/IJN.S63507. Accessed August 16, 2023
8. Generali JA, Cada DJ. Recombinant human growth hormone: HIV-related lipodystrophy. Hosp Pharm. 2014;49(5):432-434. doi:10.1310/hpj4905-432. Accessed August 16, 2023
9. Vijayakumar A, Yakar S, LeRoith D. The intricate role of growth hormone in metabolism. Front Endocrinol (Lausanne). 2011;2. doi:10.3389/fendo.2011.00032. Accessed August 16, 2023
10. Olarescu NC, Gunawardane K, Hansen TK, Moller N, Jorgensen JO. Normal physiology of growth hormone in adults. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. MDText.com, Inc.; 2000. https://www.ncbi.nlm.nih.gov/books/NBK279056/. Accessed August 16, 2023
11. Nussey S, Whitehead S. The pituitary gland. In: Endocrinology: An Integrated Approach. BIOS Scientific Publishers; 2001. https://www.ncbi.nlm.nih.gov/books/NBK27/. Accessed June 29, 2022
12. United States National Library of Medicine. MedlinePlus: GHR gene. https://medlineplus.gov/genetics/gene/ghr/. Accessed June 29, 2022
13. Smith K, Zheng L, Bosch R, et al. Treatment with recombinant growth hormone is associated with modest improvement in CD4 lymphocyte reconstitution in HIV-infected persons on antiretroviral therapy: results of ACTG A5174. AIDS Res Hum Retroviruses. 2010;26(4):425-432. doi:10.1089/aid.2009.0052. Accessed August 16, 2023
14. Napolitano LA, Schmidt D, Gotway MB, et al. Growth hormone enhances thymic function in HIV-1–infected adults. J Clin Invest. 2008;118(3):1085-1098. doi:10.1172/JCI32830. Accessed August 16, 2023
15. Plana M, Garcia F, Darwich L, et al. The reconstitution of the thymus in immunosuppressed individuals restores CD4-specific cellular and humoral immune responses. Immunology. 2011;133(3):318-328. doi:10.1111/j.1365-2567.2011.03442.x. Accessed August 16, 2023
16. National Institute of Allergy and Infectious Diseases (NIAID). Improving immune reconstitution with growth hormone in HIV-infected subjects with incomplete CD4+ lymphocyte restoration on highly active antiretroviral therapy (HAART). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 30, 2002. NLM Identifier: NCT00050921. Accessed August 16, 2023
17. Chomont, N. Effect of recombinant growth hormone on HIV reservoirs: a pilot study (CTN 298). Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. Accessed August 16, 2023
18. Treatment Action Group website. Research toward a cure trials. Accessed August 16, 2023
19. National Institute of Allergy and Infectious Diseases (NIAID). The use of recombinant growth hormone to enhance T-cell production in adults infected with HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 16, 2003. NLM Identifier: NCT00071240. Accessed August 16, 2023
20. Germans Trias i Pujol Hospital. Double strategy to induce and expand the T cell repertoire by the administration of growth hormone and vaccination in HIV-1 Infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 6, 2006. NLM Identifier: NCT00287677. Accessed August 16, 2023
21. Hvidovre University Hospital. The effect of low-dose human growth hormone therapy in HIV infected patients on highly active antiretroviral therapy (HAART). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 7, 2005. NLM Identifier: NCT00119769. Accessed August 16, 2023
22. Imperial College London. A randomised, open labelled, Phase I, safety, toxicity, and exploratory immunogenicity evaluation of therapeutic immunisation +/- IL-2, GM-CSF and growth hormone in HIV-1 infected subjects receiving highly active anti-retroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 25, 2010. NLM Identifier: NCT01130376. Accessed August 16, 2023
23. Herasimtschuk A, Downey J, Nelson M, et al. Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection. Vaccine. 2014;32(51):7005-7013. Accessed August 16, 2023

Last Reviewed: August 16, 2023