Table 1.
Overview of the development history of LAGH analogs.
| Company | LAGH analog | Modification to GH molecule | Frequency of administration | Current status | Research data |
|---|---|---|---|---|---|
| Depot Formulation | Depot Chemical | ||||
| Altus Pharmaceuticals | ALTU-238 | Long-extended release formulation using protein crystallization technology (22 kDa) (39) | 7 days | Althea acquired assets in 2010 | No further studies planned |
| Critical Pharmaceuticals | CP016 | Supercritical carbon dioxide, formed when CO2 exceeds its thermodynamic critical point, used to create the depot (22 kDa) (39) | 14 days | Company under liquidation | Evidence of ongoing studies at other corporations |
| Genentech | Nutropin Depot® | Encapulsated in biocompatible, biodegradable, polylactide-coglycolide polymer microsphere (22 kDa) (40) | 14 days | Removed from market (39) | |
| LG Life Sciences, Ltd | Eutropin Plus™(LB03002) | Microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium-chain triglycerides (22 kDa) | 7 days | Marketed in Korea for childhood GHD; approved in Europe but not marketed in the EU | Phase 3 trial in CGHD suggest non-inferiority (41), safety data from a Korean registry database in children with growth disorders (42), Phase 2 trial in children with ISS demonstrated non-inferiority and well-tolerated (43) |
| PEGylated Formulations | PEGylation prolongs in vivo mean residence time of GH, through slowing absorption and protection from proteolysis | ||||
| Ambrx | ARX201 | 30-kDa PEG added to unnatural amino acid incorporated into GH (52 kDa) | 7 days | No longer being developed (39) due to PEGylated-containing vacuoles in the epithelial cells of the choroid plexus in monkeys (44) | |
| Bolder BioTechnology | BBT-031 | Site-specific PEGylated GH analog (not available) | 7 days (planned) | Preclinical studies (45) | |
| GeneScience Pharmaceuticals Co, Ltd | Jintrolong® | 40-kDa PEG attached to GH (62 kDa) | 7 days (13, 16) | Marketed in China for CGHD | Phase 3 studies show good IGF-I profile, Phase 4 studies now ongoing |
| Novo Nordisk | NNC126-0083 | 43-kDa PEG residue attached to glutamine 141 (65 kDa) | 7 days | Unsatisfactory IGF-I profile peak and duration (46) | No longer being developed as of 2011 |
| Pfizer | PHA-794428 | Branched 40 kD PEG on N-terminus of GH (62 kDa) | 7 days | High rate of lipoatrophy at injection site (47) | No longer being developed as of 2009 |
| Pro-Drug formulation | Mechanism of conversion to active drug | ||||
| Ascendis | TransCon GH®(ACP-001) | Unmodified rhGH transiently bound to a PEG carrier molecule via a self-cleaving linker that is dependent upon pH and temperature (22 kDa) | 7 days (8, 12, 14, 18, 48) | Phase 2 studies in CGHD and AGHD showed comparable GH and IGF-I profile to daily GH dosingPhase 3 studies in CGHD showed positive growth response (49) | Completed Phase 3 study in CGHD and data submitted to FDA and EMAPhase 3 study in AGHD currently planned |
| Non-covalent albumin binding GH compound(s) | Albumin binding | ||||
| Novo Nordisk A/S | Sogroya®(NNC0195-0092) | Single-point mutation in GH, with albumin binding moiety attached (non-covalent albumin-binding properties) (50, 51) (23 kDa) | 7 days (52) | Phase 2 studies in CGHD showed comparable IGF-I profile to daily GH dosing (53)Phase 3 studies in AGHD well tolerated (54–56)Approved by the FDA in August 2020 for use in AGHD but not marketed yet | Phase 3 studies in CGHD, Phase 2 studies in SGA |
| GH Fusion Proteins | Protein fused with GH | ||||
| Ahngook Pharmaceutical Co, Ltd | AG-B1512 | Recombinant GH genetically fused to a polypeptide linker and an anti-human serum albumin Fab antibody (~72 kDa) | 14 or 28 days (57) | Preclinical studies show IGF-I level elevation sustained for 20 days | Ongoing research |
| Alteogen | ALT-P1 | rhGH fused with NexP™, recombinant a1-antitrypsin (~74 kDa) (58) | unknown | Stopped Phase 2 study in CGHD (59) | |
| Asterion | ProFuse™ GH | GH binding protein (~82 kDa) (60) | 1 month (planned) | Preclinical studies to provide intravascular stores of inactive GH | |
| Genexine and Handok | GX-H9 | rhGH fused to hybrid non-cytolytic immunoglobulin Fc portions of IgD and IgG4 (100 kDa) (61) | 7-14 days (62) | Phase 2 studies in AGHD completed (63)Phase 2 studies in CGHD showed reassuring height changes | Phase 3 studies in CGHD with twice-monthly dosing ongoing |
| Hanmi Pharmaceutical Co | LAPS rhGH(HM10560A) | Homodimeric aglycosylated IgG4 Fc fragment (~51 kDa) (64) | 7-14 days (64) | Phase 2 in AGHD show good tolerability | Phase 3 studies in AGHD (65) |
| JCR Pharmaceuticals | JR-142 | Engineered hGH fused at C-terminus with modified human serum albumin at N-terminus (~88 kDa) (66) | 7 days | Preclinical trials | Phase 1 study completed (67) |
| OPKO Health and Pfizer | Somatrogon (MOD-4023) | rhGH fused to three copies of carboxyl-terminal peptide (CTP) of hCG β-subunit (47.5 kDa) | 7 days (11, 15) | Phase 2 studies in CGHD (68), Phase 3 studies in AGHD did not meet primary endpoint of truncal fat reduction (17)Phase 3 studies in CGHD showed non-inferior improvement in height velocity with good tolerability | Phase 3 study in CGHD completed (69), and extension studies now ongoing |
| Teva | Albutropin (TV-1106) | Human serum albumin fused to N-terminus of GH (88 kDa) | 7 days (9, 10) | Studies in AGHD discontinued for unknown reason; presumed unfavorable benefit:risk profile | |
| Versartis | Somavaratan (VRS-317) | Fusion protein of rhGH and the pharmacologically inactive portion of long chains of natural hydrophilic amino acids (XTEN technology) | 7, 14 or 28 days (22) | No longer being developed as of 2017 as the Phase 3 study did not meet its primary end-point for non-inferiority comparison against daily rhGH for height velocity in CGHD (22) | |
AGHD, adults with GH deficiency; CGHD, children with GH deficiency; EMA, European Medicines Agency; EU; European Union; FDA, Food and Drug Administration; kDa, kilodalton; ISS, idiopathic short stature, PEG, poly(ethylene glycol); rhGH, recombinant human GH; SGS, small for gestational age. Table is modified from Miller BS, et al. (70).