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Keywords:

  • hemophilia;
  • inhibitors;
  • rFVIIa analog;
  • safety;
  • vatreptacog alfa (activated)

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Summary. Background: A recombinant factor VIIa analog (NN1731; vatreptacog alfa [activated]) was developed to provide safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors. Patients/Methods: This global, prospective, randomized, double-blinded, active-controlled, dose-escalation trial evaluated and compared one to three doses of vatreptacog alfa at 5, 10, 20, 40, and 80 μg kg−1 with one to three doses of recombinant FVIIa (rFVIIa) at 90 μg kg−1 in the treatment of acute joint bleeds in hemophilia patients with inhibitors. The primary endpoint comprised adverse events; secondary endpoints were evaluations of immunogenicity, pharmacokinetics, and efficacy. Results and Conclusions: Overall, 96 joint bleeds in 51 patients (> 12 years of age) were dosed. Vatreptacog alfa was well tolerated, with a low frequency of adverse events. No immunogenic or thrombotic events related to vatreptacog alfa were reported. A high efficacy rate of vatreptacog alfa in controlling acute joint bleeds was observed; 98% of bleeds were controlled within 9 h of the initial dose in a combined evaluation of 20–80 μg kg−1 vatreptacog alfa. The efficacy rate observed for rFVIIa (90%) is consistent with data from published clinical trials. The trial was not powered to compare efficacy, and further trials are needed to investigate the efficacy of vatreptacog alfa as compared with that of rFVIIa. The trial was registered at ClinicalTrials.gov (Registration Number: NCT00486278).


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

The development of neutralizing antibodies (inhibitors) against factor (F) VIII or FIX is a serious complication of replacement therapy in patients with congenital hemophilia. The use of FVIII/FIX-bypassing agents is the preferred treatment option for acute bleeds in patients with high-responding inhibitors. Two bypassing agents are currently available to treat patients with inhibitors, recombinant FVIIa (rFVIIa) (NovoSeven®; Novo Nordisk A/S, Bagsværd, Denmark) and plasma-derived activated prothrombin complex concentrate (pd-aPCC) (FEIBA VH®; Baxter AG, Vienna, Austria). Both agents have well-established efficacy and safety profiles. However, the hemostatic efficacy of these agents in patients with inhibitors does not reach the rates obtained with FVIII or FIX replacement therapy in patients without inhibitors [1–3], and may display considerable intraindividual and interindividual variability [4–6].

An rFVIIa analog was developed by Novo Nordisk with the aim of providing an improved bypassing agent offering more rapid, reliable and sustained resolution of acute bleeds in patients with hemophilia and inhibitors. This would be of clinical benefit, given the reduced need for retreatment of insufficiently treated bleeds, fewer venipunctures, reduced pain and consumption of hemostatic medication and analgesics, and less interruption to daily activities. The INN name of the active pharmaceutical ingredient of rFVIIa analog (formerly designated as NN1731) is ‘vatreptacog alfa (activated)’, and the term ‘vatreptacog alfa’ is used as the name of the drug.

Vatreptacog alfa is an activated recombinant human FVIIa analog produced biosynthetically with a CHO cell line cultured in serum-free medium. No raw materials or excipients of human or animal origin are used in the production of vatreptacog alfa. It is structurally similar to rFVIIa, with the exception of three amino acid substitutions (V158D, E296V, and M298Q) affecting the protease domain, resulting in increased tissue factor (TF)-independent activity as compared with wild-type FVIIa [7]. The mutations introduced into the vatreptacog alfa molecule mimic the effects of binding to TF, and allow the molecule to express greater proteolytic activity in the absence of TF than wild-type FVIIa. This translates into greater activity than rFVIIa on the surface of activated platelets. The enhanced platelet-dependent (TF-independent) activity of vatreptacog alfa was confirmed in several non-clinical studies [7–9].

Non-clinical studies indicate that vatreptacog alfa may provide effective, rapid and lasting cessation of bleeds [8–13]. On activated platelets, vatreptacog alfa shows increased enzymatic activity, resulting in faster and more pronounced thrombin generation, and subsequently faster and stronger clot formation with increased stability against fibrinolytic degradation [7–13]. Unlike rFVIIa, vatreptacog alfa normalizes the thrombin generation rate and clot formation in several models of hemophilia [8–13]. In a severe bleeding model in hemophilia A mice, vatreptacog alfa demonstrated significantly greater efficacy and faster bleeding resolution than rFVIIa, pd-aPCC, or rFVIII [13].

In the first human dose trial in healthy subjects, rapid thrombin generation was observed immediately after vatreptacog alfa administration [14]. Approximately 73% of vatreptacog alfa was eliminated in the initial phase, with a half-life of ∼ 20 min, and the remaining 27% was eliminated in the terminal phase, with a half-life of ∼ 3.1 h. A single dose of vatreptacog alfa appeared to be safe and well tolerated in doses up to 30 μg kg−1. No serious adverse events, including immunogenic or thromboembolic events, occurred [14].

The aim of this phase 2 trial was to evaluate the safety and preliminary efficacy of vatreptacog alfa for treatment of joint bleeds in hemophilia patients with inhibitors.

Patients, materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Trial design and objectives

The trial was a prospective, global, multicenter, randomized, double-blinded, active-controlled, dose-escalation trial, conducted from June 2007 to June 2010. The objective of the trial was to evaluate the safety and preliminary efficacy of five escalating dose levels of vatreptacog alfa (one to three doses at 5, 10, 20, 40 and 80 μg kg−1) vs. one to three doses of rFVIIa at 90 μg kg−1 in the treatment of joint bleeds in hemophilia patients with inhibitors. The randomization ratio was 4 : 1 (vatreptacog alfa/rFVIIa) in all dose tiers. Vatreptacog alfa (activated), rFVIIa and rFVIIa placebo were manufactured by Novo Nordisk (Hillerød, Denmark), and were provided as a sterile freeze-dried powder in single-use vials of 1.2 mg to be reconstituted with 2.2 mL of sterile water for injection.

Sequential dose escalation followed safety evaluations by an independent external data monitoring committee (DMC). Patients who experienced several joint bleeds during the trial period were randomized and treated in subsequent dose tiers for a maximum of five qualifying joint bleeds.

The primary endpoint was frequency of adverse events; secondary endpoints included evaluations of immunogenicity, pharmacokinetics and efficacy of vatreptacog alfa.

The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at trial initiation [15], and the International Conference on Harmonization [16] and Japanese [17] guidelines on Good Clinical Practice. The trial was registered at ClinicalTrials.gov (Number: NCT00486278).

Eligibility criteria

The trial population included adolescent and adult males above 12 years of age with congenital hemophilia A or B complicated by high-responding inhibitors to FVIII or FIX (current or historical titer above above 5 Bethesda units mL−1). Furthermore, for all patients, a documented bleeding frequency of at least two joint bleeds over 6 months or four joint bleeds over 12 months was required for inclusion in the trial.

Patients were ineligible if they had a low platelet count (< 50 000 μL−1), active pseudotumors, advanced atherosclerotic disease, severe liver disease, coagulation disorders other than congenital hemophilia, or a history of thromboembolic events.

In order for a joint bleed to qualify for trial product administration, the following had to be fulfilled: (i) the patient should not have received any intravenous hemostatic treatment for a minimum of 5 days prior to trial product administration; and (ii) the patient should not have had any other bleeds within 7 days of onset of the qualifying joint bleed. Qualifying bleeds included hemorrhages into elbows, knees, and ankles.

When experiencing a qualifying joint bleed, the patient had to attend the clinic and receive the initial dose of trial product within 3 h (+ 30 min) of onset of bleed. If the patient could not meet this requirement, the bleed was not eligible for treatment with trial product.

Trial procedures

All patients experiencing a qualifying joint bleed were randomly allocated to treatment (vatreptacog alfa or rFVIIa), and always to the lowest dose tier available.

The initial dose of trial product was to be administered in a hospital setting, and this was to be followed by continuous assessment of the bleed. If the bleeding was not controlled 3 h after initial trial product administration, up to two additional doses of trial product could be given (3-h dosing interval). Other hemostatic agents could be given according to the local standard of care if, according to the investigator, the bleed was not controlled with trial product. Patients remained at the clinic for at least 12 h after the initial dose for monitoring and evaluation of clinical response. Seven days after treatment, patients attended a follow-up visit for evaluation of general safety parameters and screening for formation of antibodies towards trial product. Screening for antibodies was repeated 28 days after each trial product administration.

Outcomes

Safety parameters were adverse events including thromboembolic events, laboratory safety data (hematology, coagulation-related parameters, clinical chemistry, and urinalysis), presence of antibodies against vatreptacog alfa, physical examination, and vital signs. Coagulation-related parameters (prothrombin fragment [F1+2], prothrombin time [PT], activated partial thromboplastin time [aPTT], D-dimers, and fibrinogen) were measured predose, and 10 min, 30 min, 1 h, 3 h, 8 h and 12 h postdose.

PT analysis was performed with STA Stago®, with STA-neoplastin and calcium as reagents. aPTT analysis was performed with Pathrombin SL reagents (Dade Behring, Deerfield, IL, USA). D-dimer levels were measured by ELISA: VIDAS® D-Dimer ExclusionTM (bioMérieux, Marcy l’Etoile, France). F1+2 was measured by ELISA: Enzygnost® F1+2 (monoclonal; Dade Behring). Fibrinogen levels were measured with the STA Stago®–Clauss method.

Samples for anti-vatreptacog alfa and anti-rFVIIa antibody screening were measured with a screening assay for detection of binding antibodies and a functional assay for detection of neutralizing antibodies. A radioimmunoassay with an 125I-labeled vatreptacog alfa/rFVIIa tracer was used to measure binding antibodies. The presence of antibodies was confirmed by inhibition with excess unlabeled vatreptacog alfa or rFVIIa. Antibody-positive samples were characterized with in vitro clotting assays for vatreptacog alfa and FVII neutralizing antibodies.

Blood sampling for assessment of the pharmacokinetic profile was obtained in a subset of patients enrolled in dose tiers 3, 4 and 5 predose and at intervals up to 12 h postdose (24 h in the United States). The FVIIa activity was determined with a one-stage clotting assay, using the Staclot® VIIa-rTF assay, and an ACL Advance® Analyzer (Instrumentation Laboratory, Milan, Italy), as described previously [14,18]. Standard pharmacokinetic endpoints were determined from the FVIIa activity profiles after a single intravenous injection, and included area under the curve (AUC)0–t, AUC, mean residence time (MRT), t½, clearance (CL) and Vss, with non-compartmental methods. In order to convert the dose in μg kg−1 to IU kg−1, the specific activities (FVIIa activity per amount of drug) of vatreptacog alfa and rFVIIa were determined in reconstituted vials.

The main preliminary efficacy endpoint was the number of bleeds successfully controlled with a single dose of trial product. Overall treatment efficacy was assessed by the need for additional hemostatic medication concomitantly with the per-protocol treatment regimen. Treatment failure was defined as bleeds where additional hemostatic medication was administered to control bleeding within 12 h of the initial dose. Assessment of efficacy also included the number of doses of trial product administered to achieve and maintain hemostatic control within the scheduled 9-h dose period, and change in pain over time after the first trial product administration.

Statistics

Data from patients exposed to at least one dose of trial product were included in the safety evaluation, and data from patients with at least one efficacy evaluation postdose were included in the efficacy evaluation.

The safety of vatreptacog alfa was based on descriptive statistics. In order to ensure an adequate number of patients for addressing the efficacy endpoints, the sample size was set to 20–25 patients per dose tier.

Statistical analyses were conducted on the efficacy endpoints. Control of bleeding with a single dose of vatreptacog alfa was analyzed by logistic regression, with treatment as a factor and target joint status and time from the start of the trial as covariates. Overall treatment efficacy within 9 h was analyzed with Fisher’s exact test, as data were categorical and the success rate was high. However, it should be noted that the trial was not powered for efficacy.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Characteristics of the cohort

Fifty-one male patients were randomized (Fig. 1) from 28 centers in 13 countries (see Appendix S1).

image

Figure 1.  CONSORT diagram showing the flow of patients and number of bleeds. FAS, full analysis set.

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At enrollment, ages ranged from 12 to 69 years, with a mean of 28 years, and the trial population included 11 patients aged 12–17 years. The majority of eligible patients had hemophilia A (n = 48). Patient demographics and baseline assessments (including hemophilia type, inhibitor level, and bleeding episode characteristics) were well balanced in the vatreptacog alfa and rFVIIa treatment groups, and were comparable between the vatreptacog alfa dose level groups.

Differences were seen, however, in baseline joint status, which was evaluated before trial product administration for each qualifying bleed. The baseline symptoms, including swelling, pain, and loss of range of motion, were more severe for bleeds treated with rFVIIa. The proportion of target joint bleeds (defined as joints with three or more bleeds in the past 6 months) was higher among vatreptacog alfa-treated bleeds (49.4%) than among rFVIIa-treated bleeds (31.6%).

Exposure to trial products

Each dose tier was planned to enroll 25 bleeds. After DMC evaluation of the first 20 bleeds in dose tier 1, the sponsor decided to discontinue this tier, as the data indicated that this dose was subtherapeutic. Dose tier 2 included the planned 25 bleeds. Because of slow recruitment of patients into the trial, dose tiers 3 and 4 were reduced from 25 to 20 bleeds each, and dose tier 5 to 12 bleeds.

Overall, 96 bleeds were treated within the trial, including 77 bleeds with vatreptacog alfa, and 19 bleeds with rFVIIa (Fig. 1).

Fifty-one patients received at least one dose of trial product(s), and 46 of these were given vatreptacog alfa (Table 1). Two patients included in dose tier 1 received higher doses than expected, owing to errors in the reconstitution of the trial product; one patient received three doses of 19.4 μg kg−1 vatreptacog alfa, and one received a single dose of 26.7 μg kg−1 vatreptacog alfa.

Table 1.   Number of exposures to trial products
 Vatreptacog alfarFVIIaTotal*
  1. rFVIIa, recombinant FVIIa. *Total exposure days is not a sum of the numbers for vatreptacog alfa and rFVIIa directly, because, for example, if a patient had one exposure to vatreptacog alfa and one to rFVIIa, he had two exposures in total, and is included under the two row for total exposure days. †Exposure days = total number of days in which patients were treated with trial product.

Number of patients461751
Exposure days† for trial product, N (%)
 125 (54.3)15 (88.2)24 (47.1)
 213 (28.3)2 (11.8)15 (29.4)
 37 (15.2)7 (13.7)
 44 (7.8)
 51 (2.2)1 (2.0)
Total dose (μg kg−1)
 Mean86214.8 
 Minimum; maximum5; 45985; 528 
Total number of doses
 Mean3.572.414.02
 Minimum; maximum1; 151; 61; 15

Evaluation of safety: adverse events, including immunogenicity

Overall, vatreptacog alfa was well tolerated, with a low frequency of adverse events in all dose groups (Table 2). Most adverse events were related to concomitant illnesses and the underlying disease (hemophilia) and consequences thereof. The type and frequency of adverse events reported following exposure to vatreptacog alfa were comparable to the well-established adverse event profile of rFVIIa.

Table 2.   Overview of adverse events
 Vatreptacog alfa, N (%), ErFVIIa, N (%), E
5 μg kg−110 μg kg−120 μg kg−140 μg kg−180 μg kg−1Total
  1. E, number of adverse events; N, number of bleeds with an adverse event; %, proportion of bleeds with adverse event; rFVIIa, recombinant FVIIa. Non-serious adverse events include events occurring from the initial dose of trial product (for treatment of bleed) until 7 days after the initial dose. Serious adverse events include all events collected from the first administration of trial product to the end of patients’ participation in the trial. *All serious adverse events had an onset more than 2 weeks (range, 16 days to almost 2 years) after treatment with trial product, and were evaluated as not related to the trial product as judged by the investigator, DMC, and sponsor.

Total bleeds16191616107719
Adverse events8 (50.0), 105 (26.3), 85 (25.0), 53 (18.8), 50 (0), 020 (26), 2810 (52.6), 11
Serious adverse events*2 (12.5), 33 (15.8), 52 (12.5), 22 (12.5), 20 (0), 09 (11.7), 122 (10.5), 3
Adverse events with onset within 7 days postdose6 (37.5), 73 (15.8), 33 (18.8), 31 (6.3), 30 (0), 013 (16.9), 168 (42.1), 8
Possibly/probably related adverse events3 (18.8), 30 (0.0), 00 (0), 00 (0), 00 (0), 03 (3.9), 31 (5.3), 1
Adverse events leading to withdrawal3 (18.8), 31 (5.3), 10 (0), 00 (0), 00 (0), 04 (5.2), 41 (5.3), 1

The majority of adverse events were rated as mild, and were judged by the investigator as unlikely to be related to the trial products. Three episodes of errors during reconstitution and administration of trial products (5 μg kg−1 vatreptacog alfa), and one episode of discomfort (after 90 μg kg−1 rFVIIa) were evaluated as being related to the trial products.

Fifteen serious adverse events were reported. All events started more than 2 weeks (range, 16–677 days) after treatment with trial product, and were evaluated as not being related to the trial product as judged by the investigator, DMC, and sponsor.

One thrombotic event was reported among patients exposed to trial product during the trial. In a 23-year-old patient exposed to vatreptacog alfa, a deep vein thrombosis of the right superficial femoral vein was reported as a serious adverse event with an onset 199 days after administration of 10 μg kg−1 vatreptacog alfa. The event, which occurred shortly after the patient suffered from cholecystitis requiring intensive care and after he had received alternative hemostatic medication according to local standard care, was judged as being unrelated to vatreptacog alfa exposure by the investigator, DMC, and sponsor.

A total of five patients were withdrawn from the trial because of adverse events, including three misdosing events (tier 1), one episode of elevated alanine aminotransferase (ALAT) level (tier 3), and the above-described venous thrombosis event (tier 2). No clinical symptoms were reported in relation to the dosing errors or the elevated ALAT value, which was present predose and was assessed as resulting from chronic hepatitis C. No formation of antibodies against vatreptacog alfa or rFVIIa was observed in any patients exposed to trial product.

Evaluation of safety: laboratory assessments

No safety concerns were revealed by any of the laboratory parameters investigated in the trial (troponin, hematology, including platelet count, biochemistry, including ALAT, and coagulation-related parameters).

No clinically relevant differences between predose and postdose values or differences between treatment groups were observed for platelet count (predose range, 126–474 × 109; 12-h postdose range, 127–502 × 109) or fibrinogen (predose range, 0.8–5.7 g L−1; postdose range, 1.0–7.4 g L−1; reference range, 2–4 g L−1). No evidence of consumption of platelets or fibrinogen was apparent in any patients.

Postdose changes of D-dimers (Fig. 2A), F1+2 (Fig. 2B), PT and aPTT were considered to be consistent with the expected pharmacologic effect of both vatreptacog alfa and rFVIIa on the coagulation system.

image

Figure 2.  Coagulation-related parameters of thrombin formation and fibrinolysis (A) Mean levels of D-dimers (ng L−1) by dose. (B) Mean levels of F1+2 (pmol L−1) by dose. Horizontal lines indicate the normal reference range. rFVIIa, recombinant FVIIa.

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Pharmacokinetic profile of vatreptacog alfa

Thirty patients had assessments of pharmacokinetic data, including a total of 42 bleeds treated in dose tier 3, 4, or 5. The FVIIa activity in plasma during the first 3 h after the initial intravenous dose of trial product is shown in Fig. 3. After the end of vatreptacog alfa infusion, FVIIa activity declined in an exponential way. A three-fold to four-fold higher peak activity was seen for 80 μg kg−1 vatreptacog alfa as compared with 90 μg kg−1 rFVIIa. At 1 h after the initial dose, mean plasma activities of vatreptacog alfa (20, 40 and 80 μg kg−1) were below the levels obtained after a single dose of 90 μg kg−1 rFVIIa.

image

Figure 3.  Mean single-dose pharmacokinetic profiles of FVIIa activity vs. time for vatreptacog alfa (20, 40 or 80 μg kg−1) and recombinant FVIIa (rFVIIa) (90 μg kg−1).

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The total exposure during the initial 30 min (AUC0–30 min) and 3 h (AUC0–t) postdose increased with increasing dose level of vatreptacog alfa, indicating dose linearity. The estimates of AUC0–t and corresponding 95% confidence intervals did not indicate any statistically significant deviations from dose linearity for vatreptacog alfa.

The clearance of vatreptacog alfa was approximately three times faster than the clearance of rFVIIa.

Evaluation of efficacy

Ninety-five bleeds were included in the evaluation of efficacy (Fig. 1).

For the majority of joint bleeds (86/95 bleeds), effective and sustained control was obtained with the per-protocol one to three doses of trial product(s) (Table 3).

Table 3.   Treatment efficacy as evaluated by number of doses of trial product administered to control bleeds within 9 h from initial dose
 Vatreptacog alfa, N (%)rFVIIa, N (%)
5 μg kg−110 μg kg−120 μg kg−140 μg kg−180 μg kg−190 μg kg−1
  1. rFVIIa, recombinant FVIIa. *Bleeds successfully controlled with one to three doses of trial product.

Total bleeds151916161019
Treatment successes*12 (80.0)16 (84.2)16 (100)15 (93.8)10 (100)17 (89.5)
Bleeds controlled with a single dose3 (20.0)3 (15.8)2 (12.5)5 (31.3)4 (40.0)6 (31.6)
Bleeds controlled with two doses5 (33.3)9 (47.4)7 (43.8)6 (37.5)4 (40.0)4 (21.1)
Bleeds controlled with three doses4 (26.7)4 (21.1)7 (43.8)4 (25.0)2 (20.0)7 (36.8)

Overall, 98% of the joint bleeds were controlled successfully with vatreptacog alfa in a combined evaluation of 20–80 μg kg−1 dose groups, as compared with 90% of bleeds treated with rFVIIa (90 μg kg−1).

The number of doses needed to obtain hemostatic control decreased with increasing dose of vatreptacog alfa, 40% of bleeds being effectively treated with a single dose of 80 μg kg−1 vatreptacog alfa (Table 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Vatreptacog alfa was well tolerated in actively bleeding hemophilia patients with inhibitors enrolled in the current trial, with a low frequency of adverse events and no safety concerns being observed at any dose level. In particular, no immunogenic or thrombotic events related to the trial product were reported. In addition, no dose relationship was evident with respect to the incidence or nature of the adverse events reported following exposure to vatreptacog alfa. Notably, the type and frequency of adverse events reported were similar to the well-established safety profile of rFVIIa in patients with hemophilia. Hence, no adverse events specific to vatreptacog alfa were identified in the trial setting.

In vatreptacog alfa, three amino acids have been substituted vs. rFVIIa. Therefore, the formation of antibody against vatreptacog alfa was closely monitored. In the current trial, 45 patients received vatreptacog alfa and were followed with antibody measurements for up to 28 days after the last trial product administration. The mean total number of vatreptacog alfa doses received during the trial was 3.6, ranging from 1 to 15. No antibody development was detected in any patients exposed to vatreptacog alfa in this trial. It should be borne in mind, however, that patients could receive vatreptacog alfa for a maximum of five bleeds with up to three doses per bleed, which may not be sufficient for the evaluation of immunogenic risk. To further evaluate the potential immunogenic risk of vatreptacog alfa, repeated assessment of potential antibody formation will be performed in future clinical trials.

One patient experienced a thrombosis of the right superficial femoral vein 199 days after administration of 10 μg kg−1 vatreptacog alfa, which was judged by the investigator, DMC and sponsor as being unrelated to the trial product. It should also be noted that his event occurred shortly after cholecystitis requiring intensive care, and after the patients had received hemostatic medication according to local standard care for treatment of a large iliopsoas bleed. Vatreptacog alfa exerts its pharmacologic action on activated platelets at the site of injury [10], and is not capable of directly activating platelets [8], so its action is limited to the site of injury. In addition, vatreptacog alfa is susceptible to the same plasma inhibitors (TF pathway inhibitor [TFPI] and antithrombin [AT]) as FVIIa, and, when bound to TF, is inhibited similarly to rFVIIa. In the absence of TF, vatreptacog alfa is inhibited more readily by TFPI and AT than rFVIIa. Approximately 70% of vatreptacog alfa is eliminated in the initial phase, with a half-life of ∼ 20 min. This rapid elimination may contribute to a low risk of thromboembolic events in patients with hemophilia following exposure to or treatment with vatreptacog alfa. As the trial included first exposure of vatreptacog alfa in bleeding patients with hemophilia, a cautious dose-escalation trial was chosen, and the trial population comprised relatively young patients (age range, 12–69 years; mean, 28 years) without any known risk factors for thrombosis/arterial thrombosis. Therefore, assessment of the thrombogenic risk of vatreptacog alfa will be further evaluated in future trials.

The pharmacokinetic data obtained in bleeding patients with hemophilia and inhibitors are consistent with the pharmacokinetic profile of vatreptacog alfa previously reported in healthy subjects [14]. The FVIIa activity declined with a biexponential decay pattern, with initial rapid elimination being followed by a less rapid elimination phase. Dose proportionality could be concluded within the dose range studied (20–80 μg kg−1). The pharmacokinetic profile obtained after intravenous administration of vatreptacog alfa was distinctly different from that obtained after the same dose of rFVIIa. As expected, the initial postdose concentration was significantly increased after administration of vatreptacog alfa. An approximately three-fold to four-fold higher initial activity for the 80 μg kg−1 dose than for 90 μg kg−1 rFVIIa was shown at 10 min postdose. At 1 h after injection of trial product, the mean plasma activities of vatreptacog alfa were below the levels obtained after rFVIIa administration. The clearance of vatreptacog alfa was approximately three times faster than the clearance of rFVIIa, as reflected in the initial half-life of vatreptacog alfa. The shorter half-life and faster clearance of vatreptacog alfa may be explained by the greater inhibition of vatreptacog alfa by AT, as suggested by recent studies [19,20].

Non-clinical data have shown that vatreptacog alfa displays increased procoagulant activity on activated platelets, resulting in a normalization of thrombin generation and formation of a stable clot [10,11]. Furthermore, animal data obtained in a mouse hemophilia model [12,13] showed that vatreptacog alfa efficiently shortened the bleeding time and reduced blood loss. This current trial expands upon these findings, showing a high efficacy rate of vatreptacog alfa in controlling acute joint bleeds at all dose levels studied, with an apparent dose relationship being observed for vatreptacog alfa efficacy endpoints.

The observed 90% efficacy rate in the rFVIIa comparator group is consistent with data from published clinical trials and experience, supporting the appropriateness of the trial design and the trial population.

In summary, a favorable safety profile of vatreptacog alfa with a low frequency of adverse events was observed in the patient population studied in this trial. In addition, preliminary efficacy evaluation showed a high efficacy rate of vatreptacog alfa, with 98% of joint bleeds being successfully controlled in a combined evaluation of the 20–80 μg kg−1 dose groups. However, as the trial was not powered for efficacy, assessment of the relative efficacy of vatreptacog alfa will need to be verified in a larger confirmatory trial.

On the basis of the clinical data obtained in the current trial and the pharmacologic characteristics, vatreptacog alfa may represent an improved option for the treatment of acute bleeding episodes in hemophilia patients with inhibitors.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

S. Ehrenforth: made substantial contributions to the conception and design of the trial; E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, S. Ehrenforth, and A. Chuansumrit: performed research/contributed to the acquisition of data; E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, S. Ehrenforth, and A. Chuansumrit: collected data; E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, S. Ehrenforth, and A. Chuansumrit: analyzed and interpreted the data; E. V. De Paula and S. Ehrenforth: co-wrote the manuscript; E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, S. Ehrenforth, and A. Chuansumrit: critically reviewed the manuscript for important intellectual content; E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, S. Ehrenforth, and A. Chuansumrit: approved the final version of the manuscript. E. V. De Paula, the lead author, assumes full responsibility for the integrity and interpretation of the data.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

We thank the 1804 investigators for their participation in this trial; a complete membership list is given in Appendix S1. The authors would like to thank H. F. Andersen (employed by Novo Nordisk A/S) for performing the statistical analyses, and L. K. Amby (employed by Novo Nordisk A/S) for providing medical writing and editorial assistance to the authors during the preparation of this manuscript.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

This trial was supported by research funding from Novo Nordisk to E. V. De Paula, K. Kavakli, J. Mahlangu, Y. Ayob, S. R. Lentz, M. Morfini, L. Nemes, S. Z. Šalek, M. Shima, J. Windyga, and A. Chuansumrit. E. V. De Paula: Novo Nordisk – consultancy, research funding, Speakers’ Bureau; Bayer – consultancy, Speakers’ Bureau. K. Kavakli: Novo Nordisk – membership of an entity’s Board of Directors or advisory committees, research funding, honorarium, costs of travel to scientific events; Baxter, Bayer – honorarium, costs of travel to scientific events; Pfizer – costs of travel to scientific events. J. Mahlangu: Novo Nordisk – honoraria, research funding, Speakers’ Bureau, costs of travel cost to scientific meeting; Bayer – honoraria, research funding, consultancy, Speakers’ Bureau, costs of travel to scientific events. Y. Ayob: Novo Nordisk – research funding. S. R. Lentz: Novo Nordisk – consultancy, research funding; Celgene– equity ownership. M. Morfini: Novo Nordisk – honoraria, research funding, Speakers’ Bureau; Bayer – honoraria, Speakers’ Bureau; Baxter – honoraria, Speakers’ Bureau; CSL Behring – honoraria, membership of an entity’s Board of Directors or advisory committees, Speakers’ Bureau; Wyeth/Pfizer – membership of an entity’s Board of Directors or advisory committees. L. Nemes: Novo Nordisk – research funding. S. Z. Šalek: Novo Nordisk – consultancy, research funding, Speakers’ Bureau; Baxter – consultancy, Speakers’ Bureau. M. Shima: Novo Nordisk – research funding; Baxter – research funding; Bayer – research funding. J. Windyga: Novo Nordisk – honoraria, research funding, Speakers’ Bureau, costs of travel to attend scientific meetings. S. Ehrenforth: Novo Nordisk – employment. A. Chuansumrit: Novo Nordisk – honoraria, research funding.

References

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  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients, materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Appendix S1. Participating principal investigators and sites.

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JTH_4549_sm_Appendix.doc29KSupporting info item

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