Safety and efficacy of a long‐acting liposomal formulation of plasma‐derived factor <scp>VIII</scp> in haemophilia A patients (2012)

Haemophilia A patients are treated by infusion of factor VIII (FVIII) concentrates, either prophylactically in order to avoid spontaneous haemorrhages or on demand to treat bleeds. Prophylactic treatment of severe haemophilia patients has been shown to provide better overall care than on-demand treatment (Manco-Johnson et al, 2007; Collins et al, 2010). The relatively short half-life of human FVIII in the bloodstream mandates a prophylactic regimen of 3 weekly infusions. This intense treatment regimen can be unacceptable to many patients and is difficult to implement. A long-acting form of FVIII would provide patients with extended protection from bleeding, fewer injections, fewer venous access complications, and better quality of life. It was previously shown that FVIII binds non-covalently to PEGylated liposomes (PEGLips) and this liposomal formulation of FVIII resulted in enhanced haemostatic efficacy in preclinical experiments (Baru et al, 2005; Dayan et al, 2009; Pan et al, 2009). Clinical trials demonstrated that liposomal formulation of FVIII was well tolerated (Spira et al, 2006, 2008; Powell et al, 2008) and its prophylactic administration to haemophilia patients prolonged the bleed-free interval between infusions (Spira et al, 2006, 2008). The present multiple-dose open-label exploratory study aimed to evaluate the safety and efficacy of a PEGLip formulation of plasma-derived FVIII (PEGLip-pdFVIII) administered as a once-weekly prophylaxis during home-treatment in haemophilia A patients. Ethical approvals were obtained from the appropriate ethics committees as well as from the Russian Ministry of Health and all subjects provided signed informed consents. PEGLip-pdFVIII is composed of two components: lyophilized high purity pdFVIII (Factane®, LFB, Les Ulis, France) and a liposomal diluent. The liposomal diluent is a 9% solution (weight lipids/volume) of a 97:3 molar ratio of the synthetic lipids 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) to 1,2 distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy(polyethyleneglycol)-2000] (MPEG 2000-DSPE), with a diameter of 80-100 nm suspended in 50 mmol/l sodium citrate, produced as previously described (Baru et al, 2005; Dayan et al, 2009). Lyophilized pdFVIII powder was reconstituted with PEGLip diluent and mixed gently for 5–10 min at ambient temp. Eleven haemophilia A patients without FVIII inhibitors were enrolled. Eligibility criteria included previous on-demand FVIII treatment, with at least 250 lifetime cumulative exposure-days (CEDs) to FVIII products and at least 25 CEDs to FVIII products during the 1-year prior to study start. Demographic characteristics of the subjects are presented in Table 1. During the 12-week study, patients received once-weekly prophylactic injections of PEGLip-pdFVIII (25–35 IU/kg FVIII, 22 mg lipids/kg of liposomes). In the initial 3-week run-in period, injections were given under medical supervision. Subsequent injections were self-administered at home over an additional 9 weeks (Fig 1). Breakthrough bleeds were treated with PEGLip-pdFVIII (26–45 IU/kg). Blood samples for assessment of safety parameters, including inhibitor testing, were collected at the beginning and the end of the study. Once-weekly PEGLip-pdFVIII prophylaxis resulted in a marked reduction in bleeding frequency relative to an on-demand treatment in all patients (Fig 1). Six out of 11 patients had no bleeds at all during the 9 weeks of home treatment. The median bleeding rate throughout this period was zero bleeds and the mean number of bleeding episodes for all 11 patients was 0·12 ± 0·05 (mean ± SEM) per week. This frequency is about 9-fold lower and significantly different (P = 0·00002, paired t-test) compared to the pre-study period (1·02 ± 0·13 bleeds per week, retrospectively). Annualization of the mean bleeding rate under once-weekly PEGLip-pdFVIII prophylaxis allows prediction of a mean bleeding rate of 6·2 bleeds/year. This figure correlates well with a bleeding rate of 6·0 annual bleeds reported under standard prophylaxis (25–40 IU/kg, 3–4 times a week) in adult haemophilia A patients (n = 54 patients; Shapiro, 2007) and with a bleeding rate of 0·52 ± 0·71 bleeds per month reported under secondary prophylaxis (Advate, Baxter BioScience, Deerfield, IL, USA), n = 107 patients; http://www.advate.com/pdf/advate_pi.pdf). It should be noted that this was an open label trial and was not randomized or blinded. A similar design was used in a clinical trial comparing the efficacy of a new FVIII concentrate (Advate) to that of previous treatment documented in the clinic's registry (Den Uijl et al, 2009). Nevertheless, additional data from a larger randomized and blinded clinical trial would be valuable to firmly support the findings of the current study. PEGLip-pdFVIII was also found to be very effective in treating bleeding episodes, as all bleeding episodes were resolved with a single infusion of PEGLip-pdFVIII (31 + 2 IU/kg, range of 26–45 IU/kg). Mean FVIII consumption over the course of the 9-week home-treatment period was 2475 ± 151 IU per week, including both prophylactic therapy and the treatment of breakthrough bleeds. This consumption was only 27% higher and not significantly different (P = 0·118, paired t-test) than FVIII consumption (1948 ± 268 IU/week) under on-demand therapy during the pre-trial period. Mean FVIII consumption including only PEGLip-pdFVIII prophylaxis was 2247 + 122 IU per week (33 IU/kg per week). This figure is 2·7-fold lower than the expected FVIII consumption under standard prophylaxis (3 weekly injections with 90 IU/kg per week) calculated for the subjects enrolled in this study (6055 ± 386 IU/week). All subjects tolerated PEGLip-pdFVIII well: No serious adverse events were recorded, no inhibitory antibodies were developed and no changes in haematological or clinical chemistry parameters were found. Two patients experienced mild complement activation-related pseudoallergy (CARPA) with the first injection. The symptoms were resolved without intervention and did not recur upon additional exposures to study drug during the run-in and home treatment periods. Similar CARPA reactions are associated with the administration of Federal Drug Administration-approved drugs containing PEGLips, such as Doxil® (Biotech, Horsham, PA, USA). Unlike IgE-mediated reactions, CARPA reactions arise at first treatment and become milder or disappear on repeated exposure (Powell et al, 2008). In summary, the results of this study demonstrate the potential of PEGLip-pdFVIII as a safe and effective once-weekly prophylactic treatment for haemophilia A patients. Such treatment is of particular importance for patients with poor venous access who have difficulties complying with the standard regimen of three prophylactic infusions per week. PEGLip-pdFVIII prophylaxis was well tolerated, resulted in a marked decrease in bleeding frequency, and consumed only marginally more FVIII than on-demand therapy. These advantages, together with the improved quality of life enabled by the once-weekly infusions, make PEGLip-pdFVIII a promising candidate for long-acting prophylactic haemophilia A therapy. The study was funded by Recoly NV. J. Spira and M. Baru designed the clinical trial. O. Plyushch, T. Andreeva, V. Zorenko, N. Zozulya, I. Velichkoi, and O.E. Zalepukhina performed the study. J. Spira, M. Baru and R. Yatuv analysed the data and wrote the paper. J.S. is employed by Recoly NV. R.Y. and M.B. are employed by Omri Laboratories Ltd. O. Plyushch, T. Andreeva, V. Zorenko, N. Zozulya, I. Velichkoi, and O.E. Zalepukhina do not have competing interests.