Abelacimab for Prevention of Venous Thromboembolism

Resident Journal Club by Chelsea Suppinger, PharmD

OVERVIEW
Citation  Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Büller HR, Raskob GE, Weitz JI; ANT-005 TKA
Investigators. Abelacimab for Prevention of Venous Thromboembolism. N Engl J Med. 2021 Aug
12;385(7):609-617. doi: 10.1056/NEJMoa2105872.
Location  Bulgaria (4 patients, 3 centers), Latvia (256 patients, 5 centers), Lithuania (92 patients, 4 centers),
Russia (1 patient, 1 center), Ukraine (59 patients, 3 centers)
Funding  Anthos Therapeutics
INTRODUCTION
Background  Patients undergoing total knee arthroplasty (TKA) are at high risk for venous thromboembolism (VTE)
 Enoxaparin, a factor Xa and thrombin inhibitor, is often administered postoperatively to reduce the
risk of VTE but is associated with bleeding risk
 Tissue factor exposed at the surgical site is thought to be the main driver of postoperative VTE through
the extrinsic pathway (Appendix A)
 The importance of the intrinsic pathway in the pathogenesis of postoperative VTE is uncertain
 Emerging evidence suggests that targeting factor XI attenuates thrombosis with little disruption of
hemostasis – factor xi antisense oligonucleotide, osocimab
 Abelacimab is a fully human monoclonal antibody that binds to factor XI locks it in an inactive
precursor formation, preventing its activation by factor XIIa or thrombin
Previous Trials  Factor XI antisense oligonucleotide for prevention of VTE (reference 1) – reducing factor XI levels in
patients undergoing elective primary unilateral TKA was an effective method for prevention of
postoperative VTE
 FOXTROT trial (osocimab) (reference 2) – fully human monoclonal immunoglobulin G1 antibody that
binds adjacent to the active site of factor XIa and prevents it from activating factor IX, study found that
postoperative osocimab was noninferior to enoxaparin and preoperative osocimab was superior to
enoxaparin
 Phase 1 trial (reference 3) -
Potential Impact  Could potentially add another option for anticoagulation and reduce risk of bleeding events
Objectives  compare the efficacy and safety of abelacimab administered postoperatively with the efficacy and
safety of enoxaparin in patients undergoing total knee arthroplasty
METHODS
Study Design  phase 2, prospective, randomized, parallel-group trial
Inclusion Criteria  18-80 years of age  Body weight of 50-130 kg
 Undergoing elective primary unilateral total knee
arthroplasty
Exclusion Criteria  Active bleeding  History of VTE
 High risk of bleeding  Estimated glomerular filtration rate < 60
 Clinically significant liver disease  Malignancy within the past year
 Uncontrolled hypertension  Clinically significant anemia
 Pregnant or nursing women
Interventions  Before surgery, patients were randomly assigned in a 1:1:1:1 ratio to receive one of three regimens of
abelacimab (30 mg, 75 mg, or 150 mg) or enoxaparin
 Abelacimab, administered in a single intravenous infusion over a period of 30 to 60 minutes, was
started 4 to 8 hours after surgery
 Enoxaparin at a dose of 40 mg administered subcutaneously once daily was started either the evening
before or approximately 12 hours after surgery
 Patients were evaluated the day before surgery and after surgery on days 1, 3, 6, and 10 and were
contacted on days 30, 50, and 110. Patients were instructed to report symptoms that were suggestive
of venous thromboembolism or bleeding
Primary Endpoint  adjudicated venous thromboembolism, defined as a composite of asymptomatic deep-vein thrombosis
(detected by mandatory unilateral ascending venography performed after surgery, between day 8 and
day 12), confirmed symptomatic venous thromboembolism (symptomatic deep-vein thrombosis of the
leg or nonfatal pulmonary embolism), fatal pulmonary embolism, or unexplained death for which
pulmonary embolism could not be ruled out
Secondary Endpoints  Individual components of composite endpoint
  Factor XI activity and the free factor XI level, which indicates the concentration of factor XI without
bound abelacimab, were quantified before surgery and after surgery on days 3, 10, and 30
Safety Endpoints  The principal safety outcome was adjudicated clinically relevant bleeding, defined as a composite of
major or clinically relevant nonmajor bleeding, from randomization until venography was completed
and from randomization through day 30.
 Also evaluated through day 110
 Hemoglobin levels and frequency of blood transfusions
Statistical Analyses  Testing for noninferiority
 Meets noninferiority if the upper limit of the 95% confidence interval for the between-group
difference in the incidence of postoperative venous thromboembolism was less than 14 percentage
points
 Need 150 patients in each trial group to meet 80% power with one-sided alpha level of 2.5% for the
primary efficacy outcome
 Cochran-Mantel-Haenszel method
RESULTS
Enrollment  412 patients enrolled from June 2020 through November 2020
 Enrollment stopped after estimated 100 patients enrolled per arm
 Slowed enrollment due to Covid19
Baseline Characteristics  Overall groups were seemingly very similar
 High percentage of females (79-87%)
 Information not provided on many baseline characteristics
Primary and Secondary Outcome Abelacimab 30 Abelacimab 75 Abelacimab 150 Enoxaparin 40 mg
Endpoints mg N = 100 mg N=98 mg N = 97 N = 100
Total VTE no. (%) 13 (13) 5 (5) 4 (4) 22 (22)
Risk difference %, -9.17 (-19.54, -16.96 (-26.21, - -18.02 (-27.06, -
CI 1.20) 7.72) 8.98)
p-value for 0.0880 0.0006 0.0002
superiority
Symptomatic VTE 0 0 0 1(1)
no. (%)
Asymptomatic 13 (13) 5 (5) 4 (4) 21 (21)
DVT no. (%)
Proximal DVT no. 1 (1) 0 0 2 (2)
(%)
Distal DVT no. (%) 12 (12) 5 (5) 4 (4) 21 (21)
NNT 12 6 6
Safety Endpoints Outcome Abelacimab 30 Abelacimab 75 Abelacimab 150 Enoxaparin 40 mg
mg mg mg
Any bleeding 2 (2) 2 (2) 0 0
event from Both clinically Both clinically
randomization relevant relevant
through nonmajor nonmajor
completion of bleeding bleeding
venography- no.
(%)
Risk difference %, 1.9 (-0.7-4.6) 1.9 (-0.7-4.5) 0
CI
Receipt of blood 6 (6) 8 (8) 9 (9) 7 (7)
transfusion – no,
(%)
NNH 52 52
AUTHORS’ CONCLUSIONS
Abelacimab reduced the risk of postoperative thromboembolism to a greater extent than conventional anticoagulants such as
enoxaparin, without increasing the risk of bleeding. Further studies are needed to determine whether anticoagulant strategies
targeting factor XI can dissociate thrombosis from hemostasis.
 GENERALIZABILITY/CRITIQUE/DISCUSSION
Journal  New England Journal of Medicine = well-respected, peer reviewed, high impact factor
Patient Population  High percentage of females
 HAS-BLED/Chads2-vasc2/Caprini scores not reported
 High risk of bleeding criteria not specified
 Many baseline characteristics not reported – comorbidities, other medications, race/ethnicity,
smoking status, BMI
Design/Intervention  Many exclusion criteria without replicable/standardized criteria and left for investigator judgement
 Several patients received the wrong dose of medication
 5 major protocol deviations (not specified)
 Enoxaparin given preoperatively and postoperatively, compared with abelacimab only given
postoperatively
 Open-label
Statistics  Study was not adequately powered
 Appropriate test for data
Endpoints/Results  Appropriately reported
OVERALL STUDY EVALUATION
Strengths  Randomized
 Multi-center
 Dose-effect relationship
Limitations  Did not meet power – could affect findings of bleeding events
 Open-label
 Many baseline characteristics not reported
 Covid19
Clinical Impact  One anticipated benefit was lower risk of bleeding which was not shown
 Superior efficacy in preventing VTE
 Would need to do an incremental cost effectiveness ratio analysis
 No reversal agent
 Once-monthly SC injection
 Not renally cleared
LEADERS’ CONCLUSION
Overall, this study contributes to data showing evidence that factor XI is an important in factor in preventing VTE following surgery.
Additionally, abelacimab was shown to be superior to enoxaparin in reducing VTE following TKA, without increasing the bleeding
risk, for this population. Further studies are needed with additional insight on patient population, comparing abelacimab to DOACs
which are becoming increasingly popular, and on possible reversal agents for abelacimab.
AUTHORSHIP
Chelsea Suppinger, PharmD
References:
1. Büller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, Segers A, Verhamme P, Weitz JI; FXI-ASO TKA Investigators.
Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015 Jan 15;372(3):232-40. doi:
10.1056/NEJMoa1405760. Epub 2014 Dec 7. PMID: 25482425; PMCID: PMC4367537.
2. Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, Metzig C, Raskob GE. Effect of Osocimab in
Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical
Trial. JAMA. 2020 Jan 14;323(2):130-139. doi: 10.1001/jama.2019.20687. PMID: 31935028; PMCID: PMC6990695.
3. Koch AW, Schiering N, Melkko S, Ewert S, Salter J, Zhang Y, McCormack P, Yu J, Huang X, Chiu YH, Chen Z, Schleeger S, Horny
G, DiPetrillo K, Muller L, Hein A, Villard F, Scharenberg M, Ramage P, Hassiepen U, Côté S, DeGagne J, Krantz C, Eder J, Stoll
B, Kulmatycki K, Feldman DL, Hoffmann P, Basson CT, Frost RJA, Khder Y. MAA868, a novel FXI antibody with a unique
binding mode, shows durable effects on markers of anticoagulation in humans. Blood. 2019 Mar 28;133(13):1507-1516. doi:
10.1182/blood-2018-10-880849. Epub 2019 Jan 28. PMID: 30692123.
4. Afshari, Arash; Fenger-Eriksen, Christian; Monreal, Manuel; Verhamme, Peter for the ESA VTE Guidelines Task Force
European guidelines on perioperative venous thromboembolism prophylaxis, European Journal of Anaesthesiology:
February 2018 - Volume 35 - Issue 2 - p 112-115
Appendix A

Appendix B