Table I.
Summary of published findings from clinical trials of new replacement factor molecules in development designed with prolonged half-lives.
| Molecule | Study | Half-life prolongation | Time to X% factor activity | Trough levels |
|---|---|---|---|---|
| Recombinant fusion protein linking FVIII to the Fc domain of human IgG1 (rFVIII Fc) | Phase I, single-dose escalation trial (25 or 65 IU/kg)19 | 25 IU/kg: 1.54-fold increase vs rFVIII; 65 IU/kg: 1.70-fold increase vs rFVIII | Time to 1%: at 25 IU/kg, 1.53-fold longer with rFVIII Fc than rFVIII; at 65 IU/kg, 1.68-fold longer with rFVIII Fc than rFVIII | NA |
| Recombinant FVIII with site-directed glycoPEGylation (N8-GP) | Phase I, single-dose escalation trial (25 U/kg, 50 U/kg and 75 U/kg)24 | 1.6-fold increase vs patients’ previous FVIII products | Time to 1%: 3.9 days (25 U/kg), 6.5 days (50 U/kg) and 5.5 days (75 U/kg) | NA |
| Sucrose-formulated rFVIII (rFVIII-FS) combined with PEGylated liposomes (BAY 79-4980) | Phase I, crossover study (rFVIII-FS infusions at 35 IU/kg with high-[22 mg/kg] or low-dose [13 mg/kg] BAY 79-4980)25 | No statistically significant differences observed between BAY 79-4980 and rFVIII-FS | NA | NA |
| GlycoPEGylated rFIX (N9-GP) | Phase I, single-dose escalation trial (25, 50 and 100 U/kg)26 | 5-fold increase vs patients’ previous FIX products | Time to 1%, 22.5 days; time to 3%, 16.2 days (post hoc estimation based on dose normalisation to 50 U/kg) | NA |
| Recombinant fusion protein linking FIX with the Fc domain of human IgG1 (rFIXFc) | Phase I/IIa single-dose escalation trial (1, 5, 12.5, 25, 50 and 100 IU/kg)27 | 3-fold increase vs that reported for current FIX products | Time to 1%: 7.34, 10.1±1.58, 12.3±2.49 days for doses of 25, 50 and 100 IU/kg, respectively. Time to 3%: 3.81, 6.28±1.11, 8.53±1.58 days for doses of 25, 50 and 100 IU/kg, respectively |
Day 7, 25 IU/kg, 1.1%, 50 IU/kg, 2.47%, 100 IU/kg, 4.65% |
| Recombinant fusion protein linking FIX with the Fc domain of human IgG1 (rFIXFc) | Phase III, non-randomised, open-label trial of prophylaxis with 50 or 100 IU/kg28 | 2.42-fold increased vs rFIX | Time to 1%: 11.2 days vs 5.1 days for rFIX. Time to 3%: 5.8 days vs 2.8 days for rFIX |
NA |
| Recombinant fusion protein linking FIX with albumin (rIX-FP) | Phase I, single-dose escalation trial (25 and 50 IU/kg)(PROLONG-9FP)29,30 | 5-fold increase vs rFIX | Trough levels maintained above 5% after 7 days for 25 IU/kg dose, and after 14 days for 50 IU/kg dose | 25 IU/kg: day 7, 7.4%, day 14, 2.5%;50 IU/kg: day 7, 13.4%, day 14, 5.5% |
| Recombinant fusion protein linking FIX with albumin (rIX-FP) | Phase I/II, safety and efficacy trial of on-demand or prophylaxis therapy (25 IU/kg)31 | PK data are under analysis but authors state that preliminary results suggest an improvement in half-life | Time to 5%: crossed much sooner with 50 IU/kg rFIX or pd-FIX (~48 h) than with 25 IU/kg rIX-FP (~156 h) | 25 IU/kg rIX-FP: day 7, 4.4% |
NA: not available; pd: plasma-derived; PEG: polyethylene glycol; PK: pharmacokinetic.