Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor ...status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors.
This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102.
Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 100% men; median age 27·0 years IQR 19·5–33·5) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 95% CI 1·0–2·7) than in the bypassing agents on-demand group (18·1 10·6–30·8), corresponding to a 90·8% (95% CI 80·8–95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported.
Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia.
Sanofi.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.
...Objectives
To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.
Patients/Methods
In this open‐label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once‐monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient‐reported outcomes (exploratory).
Results
The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean SEM) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean standard deviation 69.4 16.3 days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (−9.2 2.9) and physical health (−12.3 3.9) domain scores suggested clinically meaningful improvement.
Conclusions
Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended ...circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
In the phase 3 B‐LONG Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Subjects with Haemophilia B study, rFIXFc dosed every 1–2 weeks was safe and efficacious in previously treated ...subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long‐acting factor IX (FIX) prophylaxis. This post‐hoc analysis of B‐LONG subjects compared prophylaxis with other FIX products and rFIXFc. Pre‐ and on‐study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with rFIXFc and recombinant FIX prophylaxis. Thirty‐nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice‐weekly FIX infusions; on study, subjects infused rFIXFc once every 1–2 weeks with c. 30–50% reductions in weekly consumption. On‐study estimated mean ABRs were lower than pre‐study estimated mean ABRs. Models predicted that rFIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady‐state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving rFIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Biotherapeutic proteins represent a mainstay of treatment for a multitude of conditions, for example, autoimmune disorders, hematologic disorders, hormonal dysregulation, cancers, infectious diseases ...and genetic disorders. The technologies behind their production have changed substantially since biotherapeutic proteins were first approved in the 1980s. Although most biotherapeutic proteins developed to date have been produced using the mammalian Chinese hamster ovary and murine myeloma (NS0, Sp2/0) cell lines, there has been a recent shift toward the use of human cell lines. One of the most important advantages of using human cell lines for protein production is the greater likelihood that the resulting recombinant protein will bear post-translational modifications (PTMs) that are consistent with those seen on endogenous human proteins. Although other mammalian cell lines can produce PTMs similar to human cells, they also produce non-human PTMs, such as galactose-α1,3-galactose and N-glycolylneuraminic acid, which are potentially immunogenic. In addition, human cell lines are grown easily in a serum-free suspension culture, reproduce rapidly and have efficient protein production. A possible disadvantage of using human cell lines is the potential for human-specific viral contamination, although this risk can be mitigated with multiple viral inactivation or clearance steps. In addition, while human cell lines are currently widely used for biopharmaceutical research, vaccine production and production of some licensed protein therapeutics, there is a relative paucity of clinical experience with human cell lines because they have only recently begun to be used for the manufacture of proteins (compared with other types of cell lines). With additional research investment, human cell lines may be further optimized for routine commercial production of a broader range of biotherapeutic proteins.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased ...expression of tissue inhibitor of metalloproteinase‐1 (TIMP‐1), which blocks matrix metalloproteinase (MMP) activity. TIMP‐1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP‐1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl4), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti–TIMP‐1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl4‐treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle α‐actin (α‐SMA). Compared to controls, rats administered anti–TIMP‐1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti–TIMP‐1 resulted in a marked decrease in α‐SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP‐2. In conclusion, administration of a TIMP‐1 antibody attenuated CCl4‐induced liver fibrosis and decreased HSC activation and MMP‐2 activity. (HEPATOLOGY 2004.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Recombinant factor VIII Fc (rFVIIIFc) is a fusion protein consisting of a single B-domain-deleted (BDD) FVIII linked recombinantly to the Fc domain of human IgG1 to extend half-life. To determine if ...rFVIIIFc could be further improved by maintaining the heavy and light chains within a contiguous single chain (SC), we evaluated the activity and function of SC rFVIIIFc, an isoform that is not processed at residue R1648. SC rFVIIIFc showed equivalent activity in a chromogenic assay compared to rFVIIIFc, but approximately 40% activity by the one-stage clotting assay in the presence of von Willebrand Factor (VWF), with full activity in the absence of VWF. Moreover, SC rFVIIIFc demonstrated markedly delayed thrombin-mediated release from VWF, but an activity similar to that of rFVIIIFc upon activation in FXa generation assays. Therefore, the apparent reduction in specific activity in the aPTT assay appears to be primarily due to delayed release of FVIII from VWF. To assess whether stability and activity of SC rFVIIIFc were affected in vivo, a tail vein transection model in Hemophilia A mice was utilized. The results demonstrated similar pharmacokinetic profiles and comparable efficacy for SC rFVIIIFc and rFVIIIFc. Thus, while the single chain configuration did not promote enhanced half-life, it reduced the rate of release of FVIII from VWF required for activation. This impaired release may underlie the observed reduction in the one-stage clotting assay, but does not appear to affect the physiological activity of SC rFVIIIFc.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Recombinant factor VIII Fc fusion protein (rFVIIIFc) was safe and efficacious for control and prevention of bleeding in the multinational Phase 3 A-LONG study of previously treated ...males aged ≥12 years with severe haemophilia A. This post hoc subgroup analysis evaluated safety, efficacy, and pharmacokinetics of rFVIIIFc in Japanese subjects (n=14). Methods: Subjects received individualised prophylaxis (starting 25 IU/kg rFVIIIFc on Day 1, 50 IU/kg on Day 4; then 25–65 IU/kg every 3–5 days), weekly prophylaxis (65 IU/kg rFVIIIFc once weekly), or episodic treatment (10–50 IU/kg rFVIIIFc as needed). Primary endpoints were annualised bleeding rates (ABRs) and safety. Results: Most pharmacokinetic parameters were comparable with rFVIIIFc treatment between Japanese and non-Japanese subjects. Incremental recovery was lower in Japanese (1.7 IU/dL/IU/kg) versus non-Japanese subjects (2.2 IU/dL/IU/kg), likely related to lower average BMI and body weight for Japanese subjects. Median ABRs for Japanese subjects in the individualised prophylaxis, weekly prophylaxis, and episodic arms were 3.56, 4.34, and 25.06, respectively. Most bleeding episodes (89.5%) resolved with 1 rFVIIIFc injection. No inhibitors were reported; safety findings were comparable to non-Japanese subjects. Conclusion: rFVIIIFc was safe and efficacious for control and prevention of bleeding in Japanese subjects, with outcomes comparable to non-Japanese subjects.
The multinational Phase 3 B-LONG study demonstrated the prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) versus native recombinant factor IX (rFIX), and the safety and efficacy ...of rFIXFc for treatment of bleeding and routine prophylaxis in subjects with hemophilia B. This post hoc subgroup analysis of B-LONG evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in Japanese subjects. Previously treated males with moderately severe to severe hemophilia B (endogenous FIX ≤2 IU/dL) received weekly prophylaxis (starting at 50 IU/kg/week, with dose adjustment), individualized interval prophylaxis (starting at 100 IU/kg every 10 days, with interval adjustment), episodic treatment, or perioperative management with rFIXFc. Primary endpoints were annualized bleeding rates (ABRs) and safety. rFIXFc pharmacokinetics were comparable between Japanese subjects (n=6) and non-Japanese subjects. Median ABRs for Japanese subjects in the weekly prophylaxis (n=4) and individualized interval prophylaxis (n=2) groups were 3.27 and 4.28, respectively, which were within the range for non-Japanese subjects. For Japanese subjects, most (95.8%) bleeding episodes were resolved with 1 or 2 rFIXFc infusions, and no treatment-related adverse events or inhibitors were observed. rFIXFc was safe and efficacious for prophylaxis and treatment of bleeding in Japanese subjects with outcomes and pharmacokinetics comparable to non-Japanese subjects.
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