Table 1.
Summary of LAGH Product Development History
| Company | Product | Modification to GH Molecule (Molecular Weight) | Frequency of Administration | Current Status | Research |
|---|---|---|---|---|---|
| Depot formulation | Depot Chemical | ||||
| Altus Pharmaceuticals | ALTU-238 | Long extended-release formulation using protein crystallization technology (22 kDa) (19) | 7 d | Althea acquired assets in 2010 | No recent studies |
| Critical Pharmaceuticals | CP016 | Supercritical carbon dioxide, formed when carbon dioxide exceeds its thermodynamic critical point, used to create the depot (22 kDa) (19) | 14 d | Company under liquidation | Evidence of ongoing studies at other corporations |
| Genentech in partnership with Alkermes | Nutropin Depot | Encapsulated in biocompatible, biodegradable, polylactide-coglycolide polymer microsphere (22 kDa) (27) | 14 d | Removed from market (19) | |
| LG Life Sciences, Ltd | Declage (Eutropin Plus, LB03002) | Microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium-chain triglycerides (22 kDa) | 7 d | Marketed in Korea for CGHD; approved in Europe but not marketed in the EU | Phase 3 trials in children suggest noninferiority (47) |
| 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 d | No longer being developed (19); PEGylated-containing vacuoles in the epithelial cells of the choroid plexus in monkeys (40, 41) | |
| Bolder BioTechnology | BBT-031 | Site-specific PEGylated GH analog (not available) | 7 d (planned) | Preclinical studies (48) | |
| GeneScience Pharmaceuticals Co, Ltd | Jintrolong | 40-kDa PEG attached to GH (62 kDa) | 7 d (42, 45) | Marketed in China for CGHD | Phase 3 studies show good IGF-I profile |
| Novo Nordisk | NNC126-0083 | 43-kDa PEG residue attached to glutamine 141 (65 kDa) | 7 d | Unsatisfactory IGF-I profile peak and duration (49) | No longer being developed as of 2011 |
| Pfizer | PHA-794428 | Branched 40-kDa PEG on N-terminus of GH (62 kDa) | 7 d | High rate of lipoatrophy at injection site (44) | No longer being developed as of 2009 |
| Prodrug 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 d (50–52) | Phase 2 studies in CGHD and AGHD showed comparable IGF-I profile to daily GH dosing | Phase 3 study in CGHD ongoing and phase 3 study in AGHD planned |
| Phase 3 studies in CGHD showed preliminary positive growth response (53) | |||||
| Noncovalent albumin binding GH compound(s) | Albumin binding | ||||
| Novo Nordisk A/S | Somapacitan (NNC0195-0092) | Single-point mutation in GH, with albumin binding moiety attached (noncovalent albumin-binding properties) (54, 55) (23 kDa) | 7 d (56) | Phase 2 studies in CGHD showed comparable IGF-I profile to daily GH dosing (57) | Phase 3 studies in CGHD and extension study in AGHD ongoing |
| Phase 3 studies in AGHD well tolerated (56) | |||||
| 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 d (58) | Preclinical studies show IGF-I level elevation sustained for 20 d | Ongoing research |
| Alteogen | ALT-P1 | rhGH fused with NexP, recombinant a1-antitrypsin (~74 kDa) (59) | Unknown | Bankrupt in 2009, stopped phase 2 study in CGHD (60) | |
| Asterion | ProFuse GH | GH binding protein (~82 kDa) (61) | 1 mo (planned) | Preclinical studies to provide intravascular stores of inactive GH | |
| Genexine and Handok | GX-H9 | rhGH fused to hybrid noncytolytic immunoglobulin Fc portions of IgD and IgG4 (100 kDa) (62) | 7–14 d (63) | Phase 2 studies in AGHD completed (64) | Phase 3 studies in CGHD with twice-monthly dosing ongoing |
| Phase 2 studies in CGHD showed reassuring height changes. | |||||
| Hanmi Pharmaceutical Co | LAPS rhGH (HM10560A) | Homodimeric aglycosylated IgG4 Fc fragment (~51 kDa) (65) | 7–14 d (65) | Phase 2 in AGHD show good tolerability | Phase 3 studies in AGHD (66) |
| JCR Pharmaceuticals | JR-142 | Engineered rhGH fused at C-terminus with modified human serum albumin at N-terminus (~88 kDa) (67) | 7 d | Preclinical trials | Phase 1 study completed (68) |
| OPKO Health and Pfizer | Somatrogon (MOD-4023) | rhGH fused to 3 copies of carboxyl-terminal peptide of hCG B-subunit (47.5 kDa) | 7 d (69, 70) | Phase 2 studies in CGHD (71) Phase 3 studies in AGHD did not meet primary endpoint of truncal fat reduction (72) | Phase 3 study in CGHD (73) |
| Teva | Albutropin (TV-1106) | Human serum albumin fused to N-terminus of GH (88 kDa) | 7 d (74, 75) | Studies in AGHD discontinued for unknown reason; presumed unfavorable benefit:risk profile | |
| Versartis | Somavaratan (VRS-317) | XTEN sequence: naturally occurring hydrophilic amino acids (119 kDa) (76) | 7–30 d (77, 78) | Pediatric phase 3 trial (VELOCITY) missed noninferiority target (79) | Discontinued all studies |
| Adult trials discontinued |
Abbreviations: AGHD, GH deficiency in adults; CGHD, GH deficiency in children; PEG, poly(ethylene glycol); rhGH, recombinant human GH.