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Inhibition of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) to Accelerate Clot Lysis in Patients with Acute Pulmonary Embolism: A Phase 2 Randomized Study

1University Hospitals Leuven, Leuven, Belgium, 2Massachusetts General Hospital, Boston, United States, 3Clermont-Ferrand University Hospital, Clermont-Ferrand, France, 4Université Clermont Auvergne, Clermont-Ferrand, France, 5Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands, 6Itreas, Amsterdam, Netherlands, 7Clinical Development, Daiichi Sankyo, Basking Ridge, United States, 8Biostatistics, Daiichi Sankyo, Basking Ridge, United States, 9Clinical Development, Daiichi Sankyo, Tokyo, Japan, 10Department of Radiology, Mount Sinai School of Medicine, New York, United States, 11Department of Medicine, Cedars Sinai Medical Center, Los Angeles, United States, 12Department of Medicine - Thrombosis and hemostasis. Leiden University Medical Center, Leiden, Netherlands

Abstract Number: OC 73.1

Meeting: ISTH 2021 Congress

Theme: Venous Thromboembolism » VTE Treatment

Background: The optimal treatment of acute intermediate-risk (submassive) pulmonary embolism (PE) in hemodynamically stable patients remains unknown. Administration of currently available fibrinolytic agents reduces the risk of hemodynamic deterioration but at the expense of increased risk of major bleeding. DS-1040, a novel inhibitor of the active form of thrombin activatable fibrinolysis inhibitor (TAFIa), enhances endogenous fibrinolytic activity, without increasing bleeding risk in preclinical studies.

Aims: To evaluate the safety and efficacy of DS-1040 in patients with acute PE.

Methods: In this multicenter randomized double-blind placebo-controlled dose finding study, ascending doses of intravenous DS-1040 (20mg up to 80mg) were added to enoxaparin (1 mg/kg twice daily) in patients with acute PE. Primary safety endpoint was the number of patients with major (MB) or clinically relevant non-major bleeding (CRNMB). The efficacy endpoint included the percentage change in total thrombus volume and right to left ventricular dimensions (RV/LV ratio), both assessed by quantitative computed tomography pulmonary angiography at baseline and 12-72h after DS-1040 infusion. Endpoints were centrally assessed.

Results: Of 125 patients with sub-massive PE, 38 were randomized to placebo and 87 to DS-1040 (Table 1). Mean age was 57years, 68% were male, 94% were white, mean weight was 91kg, and mean creatinine clearance was 119ml/min. Number of bleeds were low, with no differences between DS-1040 groups and placebo group. Only one subject experienced a major bleeding (DS-1040 80mg group); no fatal or intracranial bleeding occurred (Table 1). Compared to baseline, thrombus volume was 25-45% lower after infusion, with no differences between DS-1040 groups and placebo (Figure 1). Similarly, there was no difference in the change in RV/LV ratio.

Placebo DS-1040
20mg		 DS-1040
40mg		 DS-1040
60mg		 DS-1040
80mg		 DS-1040
(all doses)
n=38 n=12 n=33 n=20 n=22 n=87
Bleeding
Number of patients with major Bleeding, n (%) 0 0 0 0 1
(4.5%)		 1
(1.1%)
Number of patients with Clinically Relevant Non-Major Bleeding, n (%) 1
(2.6%)		 0 1
(3.0%)		 0 2
(9.1%)		 3
(3.4%)
Total number of bleeds$ 10 8 5 4 5 22
Secondary Endpoints
RV/LV ratio, mean % change from baseline (SD) -8.8
(21.1)		 -3.5
(8.8)#		 -12.7
(17.1)#		 -4.2
(24.2)#		 -8.5
(15.8)#		 -8.4
(18.0)#
PE-related and all-cause death 0 0 0 1*
(5.0%)		 0 1  
(1.1%)
Recurrent PE and/or DVT** 0 1
(8.3%)		 0 1*
(5.0%)		 0 2
(2.3%)

Table 1 – Safety and efficacy endpoints across DS-1040 doses. PE: pulmonary embolism, DVT: Deep Vein Thrombosis, RV/LV ratio: ratio of right vs left ventricular diameter $ includes first and recurrent bleeding events (major, clinically relevant non-major, and minor bleeding) # no significant difference with placebo * subject was randomized but did not receive study medication ** includes worsening of index PE requiring medical intervention
Percentage change from baseline in thrombus volume in patients with acute PE treated with ascending doses of DS-1040 or placebo on top of therapeutic doses of enoxaparin (1 mg/kg twice daily).

Conclusions: In patients with acute PE, standard anticoagulation alone resulted in a considerable reduction in thrombus volume. Adding DS-1040 was safe but did not further improve thrombus resolution.

To cite this abstract in AMA style:

Vanassche T, P Rosovsky R, Moustafa F, R Büller H, Segers A, Patel I, Shi M, Miyoshi N, Mani V, Fayad Z, Schmidt J, A Grosso M, F Tapson V, Verhamme P, V Huisman M, DS1040 Study Group . Inhibition of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) to Accelerate Clot Lysis in Patients with Acute Pulmonary Embolism: A Phase 2 Randomized Study [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/inhibition-of-thrombin-activatable-fibrinolysis-inhibitor-tafi-to-accelerate-clot-lysis-in-patients-with-acute-pulmonary-embolism-a-phase-2-randomized-study/. Accessed September 21, 2023.

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