HÄMOSTASEOLOGIE - nio-kongress.denio-kongress.de/wp-content/uploads/2018/01/Tiede_Haemostaseologie.pdf · Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

HÄMOSTASEOLOGIE

Andreas TiedeKlinik für Hämatologie, Hämostaseologie,Onkologie und Stammzelltransplantation

BEST OF

2017

BEST OF

2017

Thrombose:Verlängerte Antikoagulation mit Rivaroxaban

Thrombose bei Tumorpatienten:Heparin gegen direkte orale Antikoagulanzien

FVIIIa-mimetischer Antikörper:Emicizumab bei Hämophilie A und Hemmkörper

siRNA:Fitusiran bei Hämophilie A und B

1-Jahres-Daten:AAV-GTx bei Hämophilie A und B

BEST OF

2017

NEnglJMed 2017;376:1211-22

30th Mar 2017The new england

journal of medicine

n engl j med 376;13 nejm.org March 30, 2017 1211

established in 1812 March 30, 2017 vol. 376 no. 13

The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Weitz at the Thrombosis and Athero-sclerosis Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at weitzj@ taari . ca.

* A list of the Reduced-dosed Rivaroxaban in the Long-term Prevention of Recur-rent Symptomatic Venous Thromboem-bolism (EINSTEIN CHOICE) investiga-tors and collaborators is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on March 18, 2017, at NEJM.org.

N Engl J Med 2017;376:1211-22.DOI: 10.1056/NEJMoa1700518Copyright © 2017 Massachusetts Medical Society.

BACKGROUNDAlthough many patients with venous thromboembolism require extended treat-ment, it is uncertain whether it is better to use full- or lower-intensity anticoagula-tion therapy or aspirin.

METHODSIn this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboem-bolism, and the principal safety outcome was major bleeding.

RESULTSA total of 3365 patients were included in the intention-to-treat analyses (median treat-ment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) re-ceiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confi-dence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiv-ing 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.

CONCLUSIONSAmong patients with venous thromboembolism in equipoise for continued anti-coagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.)

a bs tr ac t

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

J.I. Weitz, A.W.A. Lensing, M.H. Prins, R. Bauersachs, J. Beyer-Westendorf, H. Bounameaux, T.A. Brighton, A.T. Cohen, B.L. Davidson, H. Decousus, M.C.S. Freitas, G. Holberg, A.K. Kakkar, L. Haskell, B. van Bellen,

A.F. Pap, S.D. Berkowitz, P. Verhamme, P.S. Wells, and P. Prandoni, for the EINSTEIN CHOICE Investigators*

The New England Journal of Medicine Downloaded from nejm.org at MHH-BIBLIOTHEK on January 15, 2018. For personal use only. No other uses without permission.

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Studiendesign EINSTEIN CHOICE

Weitz et al. N Engl J Med 2017; 376: 1211-22

RGesicherte VTE nach 6-12 Monaten Behandlung

N=3396

Randomisiert, doppelt verblindet, Überlegenheit gegenüber ASSPrimärer Effektivitäts-Endpunkt: rekurrente VTE oder unklarer TodesfallPrimärer Sicherheits-Endpunkt: Majorblutung

Rivaroxaban 20 mg 1x tgl.

Rivaroxaban 10 mg 1x tgl.

ASS 100 mg 1x tgl.

12 Monate Behandlung1 Monat Nachbeobachtung

Primärer Endpunkt Effektivität



Rivaroxaban or Aspirin for Venous Thromboembolism

Figure 2. Kaplan–Meier Rates of Recurrent Fatal or Nonfatal Venous Thromboembolism and Major Bleeding.

Kaplan–Meier curves are shown for the first event of recurrent fatal or nonfatal venous thromboembolism during the individual intended treatment periods (Panel A) and for the first episode of major bleeding during the period between the administration of the first dose of a study drug and 48 hours after the administration of the last dose (Panel B). In each panel, the inset shows the same data on an enlarged y axis.

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A Fatal or Nonfatal Venous Thromboembolism

No. at RiskRivaroxaban, 20 mgRivaroxaban, 10 mgAspirin, 100 mg

110711261131

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Rivaroxaban or Aspirin for Venous Thromboembolism

Figure 2. Kaplan–Meier Rates of Recurrent Fatal or Nonfatal Venous Thromboembolism and Major Bleeding.

Kaplan–Meier curves are shown for the first event of recurrent fatal or nonfatal venous thromboembolism during the individual intended treatment periods (Panel A) and for the first episode of major bleeding during the period between the administration of the first dose of a study drug and 48 hours after the administration of the last dose (Panel B). In each panel, the inset shows the same data on an enlarged y axis.

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110711261131

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109011181103

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99710291010

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872886857

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818823800

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BEST OF

2017

NEnglJMed inpress

28th Dec 2017 T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

From the University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City (G.E.R.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam (N.E., H.R.B.), and ITREAS, Academic Research Organization (A.S.) — both in Amsterdam; the Department of Vascular Medicine and Hemostasis, University Hospitals Leuven, Leuven, Belgium (P.V.); Ottawa Hospital Research Institute, Ottawa (M.C.), London Health Sciences Centre–Victoria Hospital, London, ON (M.J.K.), University Health Network, University of Toronto, Toronto (E.Y.), and McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (J.I.W.) — all in Canada; the Department of Medicine and Aging Sciences, University G. D’Annunzio, Chieti, Italy (M.D.N.); the Department of Medicine, Division of Hematology, Uni-versity of Washington, Seattle (D.G.); Dai-ichi Sankyo Pharma Development, Bask-ing Ridge, NJ (M.A.G., M.F.M., M.S., G.Z.); Thrombosis Research Institute and Uni-versity College London, London (A.K.K.); the Department of Respiratory Disease, Hôpital Européen Georges-Pompidou, As-sistance Publique–Hôpitaux de Paris, Paris (G.M.); the Department of Internal Medi-cine, Division of Hematology, Ohio State University Wexner Medical Center, Colum-bus (T.-F.W.); and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (J.I.Z.). Address reprint requests to Dr. Raskob at the University of Okla-homa Health Sciences Center, College of Public Health, 801 NE 13th St., Oklaho-ma City, OK 73104, or at gary-raskob@ ouhsc . edu.

* A complete list of Hokusai VTE Cancer In-vestigators is provided in the Supplemen-tary Appendix, available at NEJM.org.

This article was published on December 12, 2017, at NEJM.org.

DOI: 10.1056/NEJMoa1711948Copyright © 2017 Massachusetts Medical Society.

BACKGROUNDLow-molecular-weight heparin is the standard treatment for cancer-associated ve-nous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear.

METHODSIn this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of re-current venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.

RESULTSOf the 1050 patients who underwent randomization, 1046 were included in the modi-fied intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P = 0.006 for noninferiority; P = 0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, −3.4 percentage points; 95% CI, −7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 per-centage points; 95% CI, 0.1 to 5.6).

CONCLUSIONSOral edoxaban was noninferior to subcutaneous dalteparin with respect to the com-posite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682.)

A BS TR AC T

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Gary E. Raskob, Ph.D., Nick van Es, M.D., Peter Verhamme, M.D., Marc Carrier, M.D., Marcello Di Nisio, M.D., David Garcia, M.D.,

Michael A. Grosso, M.D., Ajay K. Kakkar, M.B., B.S., Michael J. Kovacs, M.D., Michele F. Mercuri, M.D., Guy Meyer, M.D., Annelise Segers, M.D.,

Minggao Shi, Ph.D., Tzu-Fei Wang, M.D., Erik Yeo, M.D., George Zhang, Ph.D., Jeffrey I. Zwicker, M.D., Jeffrey I. Weitz, M.D., and Harry R. Büller, M.D.,

for the Hokusai VTE Cancer Investigators*

Original Article



Studiendesign Hokusai VTE Cancer

Raskob et al. N Engl J Med in press

RErwachsene mit Krebs und VTE (symptomatisch oder inzidentell)

Tag 0

Tag 5

Tag 30

Dalteparin200 IU/kg

Dalteparin150 IU/kg

Edoxaban60 mg 1x tgl.

Monat 6/12

N=1050

Offen, randomisiert, Nichtunterlegenheit (HR <1,5)Primärer Endpunkt: rekurrente VTE oder Major-Blutung

Primärer Endpunkt


T h e n e w e ngl a nd j o u r na l o f m e dic i n e

bolism or major bleeding. The rate of recurrent venous thromboembolism was numerically low-er with edoxaban than with dalteparin (7.9% and 11.3%, respectively; hazard ratio, 0.71; 95% CI, 0.48 to 1.06; P = 0.09) because of the lower rate of recurrent symptomatic deep-vein throm-bosis with edoxaban (Table 2). The 8.8% rate of recurrent venous thromboembolism at 6 months in the dalteparin group in this trial is consistent with rates reported with dalteparin in previous studies involving patients with cancer.4,16

The rate of major bleeding was significantly higher with edoxaban than with dalteparin (6.9% and 4.0%, respectively; hazard ratio, 1.77; 95% CI, 1.03 to 3.04; P = 0.04). This difference was mainly due to the higher rate of upper gas-trointestinal bleeding with edoxaban. This find-ing is consistent with results of previous studies of direct oral anticoagulants.11 The increase in upper gastrointestinal major bleeding occurred mainly in patients who had entered the trial with gastrointestinal cancer. However, the frequency of severe major bleeding (category 3 or 4; see Table 2) was similar with edoxaban and daltepa-rin. The 3.2% rate of major bleeding at 6 months in the dalteparin group in this trial is lower than previously reported rates with dalteparin.4,16

Our trial has some limitations. First, the use

of an open-label design is a potential weakness, but long-term administration of placebo injec-tions was not considered to be appropriate. To mitigate potential bias, all events were adjudi-cated by a committee whose members were un-aware of the treatment assignments. Second, the number of primary-outcome events was lower than expected; despite this limitation, noninfe-riority was established. Third, the median dura-tion of the assigned treatment was shorter with dalteparin than with edoxaban, which may have influenced the relative efficacy of the two treat-ments. However, this difference was primarily due to the inconvenience of the use of subcuta-neous dalteparin as compared with oral edoxa-ban, thus demonstrating the desirability of oral therapy in this context. In addition, the sensitiv-ity analysis of events that occurred during treat-ment in the per-protocol population confirmed the results of the primary analysis. Finally, the trial included a broad spectrum of patients with cancer who had received a wide array of cyto-toxic and biologic therapies, but the sample size limits our ability to make definitive conclusions about outcomes associated with individual tu-mor types.

In conclusion, in this trial involving patients with cancer-associated venous thromboembolism,

Figure 2. Kaplan–Meier Cumulative Event Rates for the Primary Outcome.

The primary outcome was a composite of recurrent venous thromboembolism or major bleeding. The inset shows the same data on an enlarged y axis.

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Edoxaban for Cancer-Associated Venous Thromboembolism

edoxaban was noninferior to dalteparin with re-spect to the composite outcome of recurrent ve-nous thromboembolism or major bleeding.

Supported by Daiichi Sankyo.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

References1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712-23.2. Ay C, Pabinger I, Cohen AT. Cancer-

associated venous thromboembolism: burden, mechanisms, and management. Thromb Haemost 2017; 117: 219-30.3. Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembo-

lism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-8.4. Lee AY, Levine MN, Baker RI, et al.

Figure 3. Kaplan–Meier Cumulative Event Rates for Secondary Outcomes.

Shown are cumulative event rates for recurrent venous thromboembolism (Panel A) and major bleeding (Panel B). The insets show the same data on an enlarged y axis.

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Edoxaban for Cancer-Associated Venous Thromboembolism

edoxaban was noninferior to dalteparin with re-spect to the composite outcome of recurrent ve-nous thromboembolism or major bleeding.

Supported by Daiichi Sankyo.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

References1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712-23.2. Ay C, Pabinger I, Cohen AT. Cancer-

associated venous thromboembolism: burden, mechanisms, and management. Thromb Haemost 2017; 117: 219-30.3. Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembo-

lism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-8.4. Lee AY, Levine MN, Baker RI, et al.

Figure 3. Kaplan–Meier Cumulative Event Rates for Secondary Outcomes.

Shown are cumulative event rates for recurrent venous thromboembolism (Panel A) and major bleeding (Panel B). The insets show the same data on an enlarged y axis.

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Cave: Patienten mit GI-Tumoren hatten eine besonders deutliche Steigerung der Blutungsraten

BEST OF

201731st Aug 2017The new england

journal of medicine

n engl j med 377;9 nejm.org August 31, 2017 809

established in 1812 August 31, 2017 vol. 377 no. 9

From Universitätsklinikum Bonn, Bonn, Germany (J.O.); the Haemophilia Com-prehensive Care Centre, Faculty of Health Sciences, University of the Witwaters-rand and National Health Laboratory Ser-vice, Johannesburg (J.N.M.); Genentech, South San Francisco (B.K., N.V., G.G.L.), and Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles (G.Y.) — both in California; F. Hoffmann–La Roche, Basel, Switzerland (C.S., E.A.); Children’s Hospital of Michigan, Detroit (M.U.C.); the Angelo Bianchi Bonomi He-mophilia and Thrombosis Center, Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Foundation, Ospedale Mag-giore Policlinico, Milan (E.S.); Blood-works Northwest, Seattle (R.K.-J.); Louis Pradel Cardiology Hospital, University Claude Bernard, Lyon, France (C.N.); Georgetown University Medical Center, Washington, DC (C.K.); the Department of Disorders of Hemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); and the Department of Pediatrics, Nara Medical University, Kashihara, Japan (M.S.). Address reprint requests to Dr. Oldenburg at Universitätsklinikum Bonn, Institute of Experimental Hematology and Transfusion Medicine, Sigmund-Freud-Str. 25, 53127 Bonn, Germany, or at johannes . oldenburg@ ukbonn . de.

This article was published on July 10, 2017, and updated on August 15, 2017, at NEJM.org.


BACKGROUNDEmicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in per-sons with hemophilia A with factor VIII inhibitors.METHODSWe enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emi-cizumab prophylaxis in group C.RESULTSA total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 par-ticipants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophy-laxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previ-ous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injec-tion-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombo-sis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.CONCLUSIONSEmicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann–La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials .gov number, NCT02622321.)

a bs tr ac t

Emicizumab Prophylaxis in Hemophilia A with InhibitorsJohannes Oldenburg, M.D., Ph.D., Johnny N. Mahlangu, M.D., Benjamin Kim, M.D.,

Christophe Schmitt, Pharm.D., Michael U. Callaghan, M.D., Guy Young, M.D., Elena Santagostino, M.D., Ph.D., Rebecca Kruse-Jarres, M.D., M.P.H., Claude Negrier, M.D., Ph.D., Craig Kessler, M.D., Nancy Valente, M.D.,

Elina Asikanius, M.Sc., Gallia G. Levy, M.D., Ph.D., Jerzy Windyga, M.D., and Midori Shima, M.D., Ph.D.



NEnglJMed 2017;377:809-18

VIIIaIXa XXa

Thrombin

IXaXXa

Emicizumab

Thrombin

Normal FVIII fehlend oder inhibiert

Wirkprinzip

HAVEN-1-Studie (Erwachsene mit Inhibitoren gegen FVIII)

Oldenburg et al. N Engl J Med 2017; 377: 809-18

R

Arm A:Emicizumab3 mg/kg pro Woche für 4 Wochen, dann 1,5 mg/kg pro Woche

Arm B:BedarfstherapieAPCC oder rFVIIa bei Blutungen

Arm C:Emicizumab3 mg/kg pro Woche für 4 Wochen, dann 1,5 mg/kg pro Woche

Vorherige Bedarfstherapiemit APCC oder rFVIIa

Vorherige Prophylaxemit APCC oder rFVIIa

N=35

N=19

N=24

HAVEN-1-Studie


n engl j med 377;9 nejm.org August 31, 2017814


bophlebitis (in 1 participant each) were reported in participants who had received multiple infu-sions of activated prothrombin complex concen-trate while receiving emicizumab prophylaxis before event onset. (Case details are provided in the Results section in the Supplementary Appen-dix.) Both events of thrombotic microangiopathy resolved after treatment with activated prothrom-bin complex concentrate was stopped, and nei-ther thrombotic event required anticoagulation. Two participants (1 with thrombotic microangi-opathy and 1 with thrombosis) restarted emiciz-umab treatment.

After the data cutoff for the primary analysis, thrombotic microangiopathy developed in 1 ad-ditional participant 5 days after his previous emicizumab dose and after 4 consecutive days of treatment with activated prothrombin complex concentrate for rectal hemorrhage; the rectal bleeding was recurrent and eventually fatal. As

assessed by the investigator, thrombotic micro-angiopathy was resolving at the time of death.

Of 104 participants who received emicizumab prophylaxis, 28 (27%) used activated prothrom-bin complex concentrate, 34 (33%) used recom-binant factor VIIa, and 13 (12%) used both by-passing agents (Table S4 in the Supplementary Appendix). A range of doses of recombinant factor VIIa was used, although treatment epi-sodes generally lasted for 1 day. Most use of activated prothrombin complex concentrate was less than 100 U per kilogram for 1 day, but a small number of treatment episodes averaged more than 100 U per kilogram daily and lasted more than 1 day (19 treatment events) (Table S5 in the Supplementary Appendix). The 5 partici-pants who had thrombotic microangiopathy or thrombosis did so after treatment with activated prothrombin complex concentrate that averaged more than 100 U per kilogram daily for more

Figure 1. Annualized Bleeding Rate in Trial Groups A, B, and C.

The annualized bleeding rate was calculated with the use of a negative binomial-regression model. Participants in groups A and B had previously received episodic treatment with bypassing agents; participants in group C had previously received prophylaxis with bypass-ing agents. Group D was not included in the current analysis owing to the short follow-up at the time of data cutoff.

Annu

aliz

ed R

ate

of B

leed

ing

Even

ts(9

5% C

I)

30

20

25

15

10

5

0Group A

Emicizumab Prophylaxis(N=35)

Group BNo Prophylaxis

(N=18)

Group CEmicizumab Prophylaxis

(N=49)

87% Difference in annualized rate of treated bleeding events(risk ratio, 0.13; P<0.001)

All bleeding events

Bleeding events treatedwith bypassing agents

Treated events of spontaneous bleeding

Treated eventsof joint bleeding

Treated events oftarget-joint bleeding

6.7 (2

.0–22

.4)

5.5 (3

.6–8.6

)

2.9 (1

.7–5.0

)

1.3 (0

.7–2.2

)

0.8 (0

.3–2.2)

0.1 (0

.0–0.6

)

23.3

(12.3

–43.9)28

.3 (1

6.8–47

.8)

16.8

(9.9–

28.3)

3.0 (1

.0–9.1

)6.5

(3.4–

12.4)

5.1 (2

.3–11

.2)

3.1 (1

.2–8.0

)

0.6 (0

.2–1.5

)

0.3 (0

.1–1.0

)




Emicizumab Prophylaxis in Hemophilia A with Inhibitors

in association with emicizumab prophylaxis alone. Two events of thrombotic microangiopathy resolved completely (the third participant died from rectal hemorrhage after the primary analy-sis), and the thrombotic events did not require anticoagulation. Recovery from these events oc-curred in the continued presence of emicizumab in plasma owing to its long half-life,16 and no recurrence of thrombotic microangiopathy or thrombosis was seen in the two participants who restarted emicizumab.

Synergistic thrombin generation has previ-ously been shown with activated prothrombin complex concentrate in combination with emiciz-umab in vitro and in vivo.17 Substrates for emiciz-umab to form the intrinsic tenase complex are supplied by activated prothrombin complex con-centrate, along with other activated and nonacti-vated coagulation factors that have half-lives of up to 60 hours and can accumulate with multi-ple doses.18 Although the data are scant, the combined use of activated prothrombin complex concentrate and emicizumab prophylaxis ap-pears to be associated with a substantial risk of toxic effects, which may limit the usefulness of this bypassing agent in patients who bleed while receiving emicizumab prophylaxis.

No antidrug antibodies were detected; how-ever, two participants had pharmacokinetic pro-files with declining emicizumab concentrations over time that were potentially indicative of an-tidrug antibodies. One participant had no bleed-ing events while receiving emicizumab prophy-laxis, and the other is being monitored after an increase in the dose of emicizumab, which oc-curred shortly before the primary analysis. Both participants remained in the trial; longer follow-up will provide further insight into the efficacy and pharmacokinetic outcomes of these partici-pants.

Stable trough plasma concentrations of emi-cizumab were observed after 4 weeks of loading doses and were sustained with weekly mainte-nance doses throughout the trial. With this previ-ously untested dosing regimen, which was de-termined by means of pharmacokinetic and pharmacodynamic modeling, the trough con-centrations that were observed (>50 µg per mil-liliter) are expected to result in a bleeding rate of zero among at least 50% of the participants.19

Limitations of the trial include its open-label nature, which may have affected the results for

end points with respect to health-related quality of life and health status; however, because all results for primary and secondary end points were positive, these consistent results probably reflect true differences between the randomly assigned groups. Selection bias for groups C and D should also be considered. At the time of en-rollment, participants had had at least six and two bleeding events during the previous 24 weeks of prophylactic and episodic treatment with by-passing agents, respectively. Thus, these partici-pants could potentially show a more substantial decrease in bleeding events over the course of the trial than participants with lower pretrial bleeding rates, had they been eligible. Finally, follow-up for some participants (in groups C and D) was less than 24 weeks; however, all randomly assigned participants had at least 24 weeks of follow-up for the primary and second-ary end points, and durable efficacy has been shown for up to 2 years in the phase 1 study.20

In conclusion, emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis or previous prophylactic treatment with bypassing agents among patients with hemophilia A with inhibi-tors, and it improved health-related quality of life. Emicizumab was safe when administered alone or in conjunction with recombinant factor VIIa

Figure 3. Observed Trough Plasma Concentrations of Emicizumab over Time with Once-Weekly Dosing (102 Patients).

As determined by pharmacokinetic and pharmacodynamic modeling, emi-cizumab doses of 1.5 mg per kilogram of body weight per week were pre-dicted to result in trough plasma concentrations of emicizumab of 45 µg per milliliter (dashed line). I bars indicate standard deviations.

Mea

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Interaktion mit APCC


!8 Patienten erhielten APCC >100 U/kg für >24 h

Bei 5 von 8 thromboembolische Ereignisse:• Thrombotische Mikroangiopathie (n=3)• Atypisch lokalisierte Venenthrombosen (n=2)

BEST OF

2017T h e n e w e ngl a nd j o u r na l o f m e dic i n e


The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Pasi at the Haemophilia Centre, Royal London Hospital, London E1 1BB, United Kingdom, or at k . j . pasi@ qmul . ac . uk.

This article was published on July 10, 2017, at NEJM.org.


BACKGROUNDCurrent hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (en-coded by SERPINC1), is in development to address these and other limitations.

METHODSIn this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 par-ticipants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitu-siran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The partici-pants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.

RESULTSNo thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran in-creased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrom-bin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.

CONCLUSIONSOnce-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in partici-pants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605.)

A BS TR AC T

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

K.J. Pasi, S. Rangarajan, P. Georgiev, T. Mant, M.D. Creagh, T. Lissitchkov, D. Bevan, S. Austin, C.R. Hay, I. Hegemann, R. Kazmi, P. Chowdary,

L. Gercheva-Kyuchukova, V. Mamonov, M. Timofeeva, C.-H. Soh, P. Garg, A. Vaishnaw, A. Akinc, B. Sørensen, and M.V. Ragni

Original Article



31st Aug 2017

NEnglJMed 2017;377:819-28

WirkprinzipT h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 373;4 nejm.org July 23, 2015390

cyte, it was found that attaching an N-acetyl-galactosamine (GalNAc) moiety to the siRNA improved its binding to the hepatocyte through the asialoglycoprotein receptor and also pro-tected it from digestion by RNases. Sehgal et al. used this approach when they administered anti-thrombin III siRNA subcutaneously to wild-type mice, to a mouse model of hemophilia A, and to nonhuman primates and found a dose-depen-dent reduction in antithrombin III. In fact, they observed a 50% reduction in antithrombin III3 in nonhuman primates after a single weekly subcu-taneous dose of the siRNA. In mouse and non-human primate models of hemophilia A, they found dose-dependent correction of the activated

partial thromboplastin time and improvement in thrombin generation, as well as a reduction in bleeding, with no thrombosis.3

What does this new therapeutic agent mean for patients with hemophilia? The potential to reduce bleeding in patients with hemophilia with or without inhibitors with a single weekly sub-cutaneous dose could be life-changing. Better protection from bleeding achieved with a simple once-weekly, less invasive, subcutaneous injec-tion would be transformative. Assuming that similar hemostatic effects are shown in patients with hemophilia who are receiving antithrombin III siRNA, the cost will be an important consid-eration in the decision to adopt such a therapy,

Figure 1. Silencing Antithrombin III (ATIII) to Promote Hemostasis.

On the right, small interfering RNA (siRNA) conjugated to N-acetylgalactosamine (GalNAc) binds to the hepatocyte receptor asialoglyco-protein (ASPGR), which enables entry into the cell, endocytosis, and, after pairing with ATIII messenger RNA (mRNA), inhibition of post-transcriptional ATIII synthesis. RNA silencing is triggered when double-stranded RNA is cleaved into siRNA, and the sense strand of the siRNA is removed, leaving an antisense strand complementary to the target gene, which silences the gene. The graph indicates significant inhibition of ATIII synthesis, which results in unchecked thrombin formation in the coagulation cascade (inset on the left); this allows unchecked physiological fibrin clot formation. Values on the y axis are proportions of ATIII levels relative to predose levels. RISC denotes RNA-induced silencing complex.

COAGULATION CASCADE(occurs in circulation)

HEPATOCYTE

NUCLEUS

Intrinsic System Extrinsic System

Factor XI Factor XIa

Factor IXaFactor IX

Factor X Factor Xa

Factor II

Factor I Factor Ia(fibrin)

Factor IIa(thrombin)

Factor XIIa

Surface contact Tissue factor

PF-3Ca2+

PF-3Ca2+

Factor VIII

PF-3Ca2+

Factor V

Factor XII Factor VII Factor VIIa

ATIII siRNA

Endosome

Vesicle

GalNAc

ASPGR

RISC

RecyclingASPGR

ATIII mRNA

No ATIII synthesis

Reduced inhibition

ATIII

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1.00.80.60.40.2

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Rela

tive

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I Lev

el



Ragni N Engl J Med 2017; 373: 389

Wirkprinzip

Sehgal et al. Nat Med 2015; 21: 492-7

AT-Depletion steigert Thrombinbildungin Plasma von Patienten mit Hämophilie A und B

Fitusiran Phase 1/2

Part AGesunde MännerFitusiran 0,03 mg/kg oder Placebo

Part BHämophilie A oder BFitusiran 0,015 à 0,045 à 0,075 mg/kg 1x wöchentlich

Part CHämophilie A oder BFitusiran 0,225 à 0,45 à 0,9 à 1,8 mg/kg à 80 mg abs. 1x monatlich

Pasi et al. N Engl J Med 2017; 377: 819-28

Pharmakokinetik



RNAi Ther apy Targeting Antithrombin in Hemophilia

dose of 80 mg of fitusiran, the mean maximum lowering of the antithrombin level was 87±1% (Fig. 2C). A summary of dose-dependent anti-thrombin lowering according to dose cohort in Parts A, B, and C is shown in Figure S2 in the Supplementary Appendix. The minimum post-dose antithrombin level that was observed during the study was 9.8% (in the 80-mg cohort). After the discontinuation of fitusiran, the rate of re-covery in the antithrombin level had a mean slope of 10 to 15% per month (Fig. 2C).

The association between the antithrombin level and thrombin generation showed that a low-ering of the antithrombin level led to increased thrombin generation in the participants with hemophilia (Fig. 3). This relationship was similar in participants with hemophilia A and in those with hemophilia B. A reduction in the anti-thrombin level by more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy vol-unteers (Fig. S3 in the Supplementary Appendix).

In a post hoc exploratory analysis to deter-mine the effect of monthly fitusiran administra-tion on bleeding rates, there were fewer bleeding episodes per month after treatment with fitu-siran than before treatment, a finding that was consistent with the reduction in antithrombin levels (Table S4 in the Supplementary Appendix). All the bleeding episodes were successfully man-aged with factor replacement (Table S5 in the Supplementary Appendix).

Safety OutcomesAdverse events were graded as mild, moderate, or severe. An adverse event was further classified as a serious adverse event if it met prespecified criteria.

Three healthy volunteers received a single dose of fitusiran at 0.03 mg per kilogram (one received placebo), and a total of five mild adverse events were reported in two of the volunteers who re-ceived fitusiran. Four of these events were con-sidered by the investigators to be either not re-lated or unlikely to be related to fitusiran, and one event (headache) was considered to be pos-sibly related. All the adverse events resolved spon-taneously. The adverse events that were reported in Part A are summarized in Table S6 in the Supplementary Appendix. There were no serious adverse events or discontinuations among the healthy volunteers.

In Parts B and C, 25 participants with hemo-philia received fitusiran, and 19 participants (76%) reported having an adverse event during the study. Most of these events were mild to moderate in severity. (All the adverse events that occurred in at least 2 participants who received fitusiran are shown in Table 2, and in Table S7 in the Supplementary Appendix.) Nine of 25 par-ticipants (36%) in Parts B and C had adverse events that were considered to be related to fitu-siran. Of these events, the most common were injection-site pain (in 6 participants [24%]), in-jection-site erythema (in 4 participants [16%]), and an increased alanine aminotransferase level (in 2 participants [8%]). More adverse events were reported in the cohort that received the 80-mg fixed dose than in the other cohorts, but this in-creased rate appears to have been driven mainly by a higher reporting of injection-site reactions and potentially by a larger group size (6 partici-pants), which led to a higher number of adverse events in a single participant. Participants who received the higher weight-based dose of 1.8 mg per kilogram had a lower frequency of adverse events, so no clear conclusion with respect to the relationship between dose and adverse events can be made.

Three participants in Part C had adverse events that were graded as severe during the study. One participant who was receiving 0.45 mg of fitu-siran per kilogram had severe, nonserious hy-pertriglyceridemia, tooth fracture, and toothache.

Figure 1. Pharmacokinetic Characteristics of Fitusiran in Plasma after Subcutaneous Injection.

Shown are mean plasma levels of fitusiran over time after a single subcuta-neous injection, according to dose. The I bars represent standard errors, which were calculated only for cohorts with at least two participants.

0.03 mg/kg0.045 mg/kg0.075 mg/kg

1.8 mg/kg80 mg

0.9 mg/kg

0.015 mg/kg

0.225 mg/kg0.45 mg/kg

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Hour



Pharmakodynamik




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B Participants with Hemophilia on Once-Weekly Regimen (Part B)

C Participants with Hemophilia on Once-Monthly Regimen (Part C)

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Fitusiran, 0.03 mg/kg (N=3)

0.015 mg/kg (N=3)

0.045 mg/kg (N=6)

0.075 mg/kg (N=3)

0.45 mg/kg (N=3)

80 mg (N=6)

0.225 mg/kg (N=3)

1.8 mg/kg (N=3)0.9 mg/kg (N=3)





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0.015 mg/kg (N=3)

0.045 mg/kg (N=6)

0.075 mg/kg (N=3)

0.45 mg/kg (N=3)

80 mg (N=6)

0.225 mg/kg (N=3)

1.8 mg/kg (N=3)0.9 mg/kg (N=3)





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0.015 mg/kg (N=3)

0.045 mg/kg (N=6)

0.075 mg/kg (N=3)

0.45 mg/kg (N=3)

80 mg (N=6)

0.225 mg/kg (N=3)

1.8 mg/kg (N=3)0.9 mg/kg (N=3)



Thrombinbildung



RNAi Ther apy Targeting Antithrombin in Hemophilia

A second participant, who was receiving 1.8 mg of fitusiran per kilogram, had a severe, serious event of viral pneumonia. A third participant who was receiving the fixed dose of 80 mg of fitusiran had a severe, nonserious event of non-cardiac chest pain that was considered to be possibly drug-related on day 44 and which led to study discontinuation on day 45 (after the last dose of fitusiran had been received on day 28). The chest pain was accompanied by elevations in levels of C-reactive protein, alanine aminotrans-ferase, aspartate aminotransferase, and D-dimer. Extensive evaluation did not reveal any substan-tial medical abnormalities; pulmonary embolism, portal-vein thrombosis, and deep-vein thrombo-sis were ruled out on repeated computed tomo-graphic angiography and Doppler ultrasonogra-phy of the liver and lower limbs. Serologic results for viral hepatitis were negative. Ultrasonography of the abdomen showed the presence of gall-bladder sludge, but a definitive diagnosis was not made. The event resolved with the use of analgesics and antacids, and laboratory values normalized.

Of the 25 participants in Parts B and C, 2 (8%) reported one serious adverse event each. One of these events was a reactivation of hepati-tis C viral infection in a participant who had received 0.45 mg of fitusiran per kilogram (see the Supplementary Appendix for details), and the other was the above-mentioned viral pneumonia. Neither serious adverse event led to a discontinu-ation of fitusiran.

There were no clinically significant changes on physical examination, in vital signs, or in elec-trocardiographic measurements in any participant. Asymptomatic, transient elevations in the alanine

aminotransferase level (>1.5 times the upper limit of the normal range or >1.5 times the base-line value [in participants with a baseline value that was above the upper limit of the normal range]) were observed in 9 of 25 participants (36%), but no events were associated with an increased bilirubin level or led to treatment dis-continuation (Figs. S4 and S5 in the Supplemen-tary Appendix). Of these 9 participants, 8 had peak elevations that were less than 3 times the upper limit of the normal range; 1 participant had an increase of more than 3 times the upper limit of the normal range in association with the above-mentioned chest pain. The 9 participants with elevated alanine aminotransferase levels were distributed across the dose cohorts, and no clear dose−response relationship could be determined (Table S8 in the Supplementary Appendix). Eight of the participants with an increased alanine aminotransferase level had a medical history of hepatitis C infection and had not received cura-tive treatment. Elevations in the D-dimer level were observed in some participants; however, we were

Figure 3. Relationship between Antithrombin Level and Thrombin Generation.

Shown are paired antithrombin levels and peak values for thrombin genera-tion in all the participants with hemophilia A or B and in healthy volunteers for whom data were available. The dashed line shows the median baseline values for the participants with hemophilia A or B. Antithrombin levels were determined relative to a standard human plasma reagent with a de-fined antithrombin activity level calibrated against a World Health Organi-zation reference.

Peak

Thr

ombi

n Le

vel (

nM)

250

150

200

0

50

100

0 20 40 60 80 100 120 140

Antithrombin Level (%)

Healthy volunteersHemophilia AHemophilia BHemophilia A and B atbaseline (median)

Figure 2 (facing page). Pharmacodynamic Characteristics of Fitusiran.

Shown are the mean plasma antithrombin levels among the study participants, normalized to the activ-ity level at baseline, after a single injection of fitusiran in healthy volunteers (Panel A) and in participants with hemophilia after three once-weekly injections (Panel B) and after three once-monthly injections (Panel C). The arrows below the graph indicate the timing of the injections. The I bars represent standard errors, which were calculated only for cohorts with at least two participants.



BEST OF

2017The new england

journal of medicine

n engl j med 377;23 nejm.org December 7, 2017 2215

established in 1812 December 7, 2017 vol. 377 no. 23

The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. George at the Children’s Hospital of Philadelphia, 3401 Civic Center Blvd., Rm. 5016, Philadelphia, PA 19106, or at georgel@ email . chop . edu.


BACKGROUNDThe prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia.METHODSWe infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengi-neered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.RESULTSNo serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P = 0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P = 0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treat-ment. One participant, who had substantial, advanced arthropathy at baseline, adminis-tered factor for bleeding but overall used 91% less factor than before vector infusion.CONCLUSIONSWe found sustained therapeutic expression of factor IX coagulant activity after gene trans-fer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092.)

a bs tr ac t

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

L.A. George, S.K. Sullivan, A. Giermasz, J.E.J. Rasko, B.J. Samelson-Jones, J. Ducore, A. Cuker, L.M. Sullivan, S. Majumdar, J. Teitel, C.E. McGuinn, M.V. Ragni, A.Y. Luk, D. Hui, J.F. Wright, Y. Chen, Y. Liu, K. Wachtel,

A. Winters, S. Tiefenbacher, V.R. Arruda, J.C.M. van der Loo, O. Zelenaia, D. Takefman, M.E. Carr, L.B. Couto, X.M. Anguela, and K.A. High



NEnglJMed 2017;377:2215-27

7th Dec 2017

SPK-9001

George et al. N Engl J Med 2017; 377: 2215-27

• AAV-basierter Vektor• Kodon-optimiert• FIX-Variante „Padua“ R338L mit 5fach höherer Aktivität

• Applikation 5x1011 vg/kg KG

• Steroide im Fall von Transaminasen-Anstieg bei Anti-Kapsid-Immunreaktion, um Elimination transduzierterHepatozyten zu verhindern

Effektivität über 1 Jahr


Hemophilia B Gene Ther apy with Factor IX Variant

for sensitive immunomonitoring techniques, which we used during the at-risk window. Our data indicate that the combined evaluation of liver-function studies and assays to assess factor IX coagulant activity aid in the timely detection and appropriate management of a capsid-directed immune response and can be completed in any clinical laboratory. ELISPOT assay results pro-vided meaningful data to confirm the cause of elevations in the aminotransferase levels but would be impractical for use in widespread adoption of this therapy.

Despite varied trial courses among the 10 par-ticipants, the mean steady-state factor IX coagu-lant activity was 33.7±18.5% of the normal value, and a therapeutic effect at this dose was ob-served in all the participants, even those who had preexisting (low titer) neutralizing antibod-ies or cellular immune responses that occurred after infusion. It is not clear what the basis was for the finding that the factor IX coagulant activ-ity in Participant 9 was approximately 2 times as high as that in the other participants. Although the mechanism of transduction with AAV vectors has been extensively studied, many aspects, in-cluding binding to cell-surface receptors, entry by means of endosomal pathways, endosomal escape, uncoating, and entry into the nucleus, are poorly understood.29,30 The range of levels of factor IX coagulant activity that we observed may represent the inherent variability in transgene-derived protein levels with this new class of

therapeutic agents. The two participants who had a capsid-directed immune response also had the most rapid initial rise in factor IX coagulant activity. More extensive experience will be re-quired in order to determine whether these events occurred by chance or represent a useful predictor of immune response. It is also unclear whether the immune response somehow facili-tated vector expression. In addition, the plateau in the factor IX coagulant activity in Participant 6, which was lower than that in the other par-ticipants, is consistent with an expected reduc-tion in hepatocyte transduction in the presence of the 1:1 titer for neutralizing antibody (antic-ipated to neutralize 50% of vector) to AAV (Table 1); this finding supports the hypothesis that our AAV neutralizing antibody assay is sen-sitive. A current limitation of in vivo AAV gene transfer is the existence of AAV neutralizing anti-bodies in approximately 30 to 40% of the popu-lation, who would not be eligible for this therapy as it is currently formulated.31 A sensitive AAV neutralizing antibody assay is essential for the identification of patients with a negative titer and those with low titers, who may still benefit from this therapy but who would be predicted to have a transgene expression level that is lower than the level in patients with a negative titer, given the current vector formulation.32

We found consistent clinical outcomes despite the baseline heterogeneity of the participants, including the extent of hemophilic arthropathy,

Figure 1. Factor IX Activity after One Peripheral Infusion of SPK-9001 in the Eight Participants Who Did Not Have an Adeno-Associated Viral Capsid-Directed Immune Response.

The vector SPK-9001 was administered at a dose of 5×1011 vector genomes per kilogram of body weight.

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George et al. N Engl J Med 2017; 377: 2215-27

BEST OF

2017

NEnglJMed 2017;377:2519-30

28th Dec 2017

The new england journal of medicine


established in 1812 December 28, 2017 vol. 377 no. 26

From Hampshire Hospitals NHS Foun-dation Trust, Basingstoke (S.R.), Univer-sity Hospitals Birmingham NHS Founda-tion Trust, Edgbaston (W.L.), Cambridge University Hospital NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge (D.P.), and the Centre for Haemostasis and Thrombosis, St. Thomas’ Hospital (B.M.), Imperial College London and NIHR Clinical Research Facility at Impe-rial College Healthcare NHS Trust (M.L.), and Barts and the London School of Medicine and Dentistry (K.J.P.), London — all in the United Kingdom; and Bio-Marin Pharmaceutical, Novato (L.W., H.Y., C.V., W.Y.W.), and private consultant, La Jolla (G.F.P.) — both in California. Ad-dress reprint requests to Dr. Pasi at the Royal London Hospital Haemophilia Cen-tre, 2nd Fl. Central Tower, Whitechapel, London E1 1BB, United Kingdom, or at k . j . pasi@ qmul . ac . uk.

This article was published on December 9, 2017, at NEJM.org.


BACKGROUNDPatients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene trans-fer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A.

METHODSWe infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain–deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled se-quentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks.

RESULTSFactor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary ad-verse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected.

CONCLUSIONSThe infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceuti-cal; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.)

a bs tr ac t

AAV5–Factor VIII Gene Transfer in Severe Hemophilia ASavita Rangarajan, M.B., B.S., Liron Walsh, M.D., Will Lester, M.B., Ch.B., Ph.D., David Perry, M.D., Ph.D.,

Bella Madan, M.D., Michael Laffan, D.M., Hua Yu, Ph.D., Christian Vettermann, Ph.D., Glenn F. Pierce, M.D., Ph.D., Wing Y. Wong, M.D., and K. John Pasi, M.B., Ch.B., Ph.D.



AAV5-hFVIII-SQ

Rangarajan et al. N Engl J Med 2017; 377: 2519-30

• AAV-5-basierter Vektor• Leberspezifischer Hybrid-Promoter• Kodon-optimierter, B-Domän-deletierter Faktor VIII

• Applikation bis zu 6x1013 vg/kg KG

• Prophylaktische Steroidtherapie zur Verhinderung einer Anti-Kapsid-Immunreaktion

Wirksamkeit über 1 Jahr

n engl j med 377;26 nejm.org December 28, 20172526


level was below the limit of quantitation at week 52. The samples from Participant 2 (in the inter-mediate-dose cohort) indicated one negative re-sult in the feces compartment and a blood level above the limit of quantitation at week 52.

In the high-dose cohort, residual levels of vector DNA were present in all seven partici-pants at week 52 in blood, with all values above the limit of quantitation. The fastest clearing bio-logic fluid was urine, with all participants having urine cleared at or before 28 weeks (range, 6 to 28) (Fig. 4). Four of the seven participants had semen cleared at or before 36 weeks (range, 16 to 36); of the remaining three participants, one had two consecutive negative results (this par-ticipant had semen cleared at week 56 when three consecutive negative results were obtained), and two had levels below the limit of quantitation in semen at week 52. On further investigation, we found that vector DNA was not present in puri-fied sperm cells that were obtained from these two participants, which ruled out the risk of

inadvertent germline modification. All the par-ticipants in the high-dose cohort had samples showing that saliva was cleared at or before 52 weeks (range, 40 to 52). No participant in the high-dose cohort had a sample showing that fe-ces was cleared at week 52, but all the levels were below the limit of quantitation. The household contacts of the participants were not examined.

Discussion

We report the results of a phase 1–2, dose-esca-lation study to assess the safety and efficacy of a single peripheral infusion of AAV5-hFVIII-SQ, a codon-optimized AAV5 vector encoding B-domain–deleted human factor VIII, in nine men with se-vere hemophilia A. These changes in the vector and the gene resulted in successful gene transfer in participants with hemophilia A, despite the large size of the coding region.

Increases in the factor VIII activity levels were dose-dependent, with all seven participants in

Figure 2. Factor VIII Activity Levels in the High-Dose Cohort.

Factor VIII values are from the one-stage assay performed by a central laboratory (Esoterix), with normal values of 50 to 150 IU per deciliter (shaded area). Data were available for all seven participants in the high-dose cohort, ex-cept that data were not available for Participant 7 at week 32. The plot is based on the median values of factor VIII activity within 4-week windows for each participant. The horizontal line within each box indicates the median value among the participants. The lower and upper boundaries of the box represent the 25th and 75th percentiles, re-spectively. The ends of the whisker lines represent the minimum and maximum values within 1.5 times the inter-quartile range from the lower and upper box boundaries. Mean values are indicated by diamonds. Factor VIII activity levels below the limit of quantitation were imputed as being 0.5 IU per deciliter. Factor VIII activity levels within a 72-hour period since the last consumption of factor VIII were excluded. Data points beyond the range (i.e., 1.5 times the interquartile range from the lower and upper box boundaries) were considered to be outliers and are marked with an ×.

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Rangarajan et al. N Engl J Med 2017; 377: 2519-30

6x 1013 vg/kg KG

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