Perosphere and Daiichi Sankyo enter into a clinical trial agreement

Perosphere Inc. and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that they have entered into a clinical trial agreement under which Daiichi Sankyo will support and co-sponsor a phase 1 clinical study testing the safety, tolerability and effectiveness of PER977 to reverse the anticoagulant activity of edoxaban, Daiichi Sankyo’s investigational oral, once-daily, direct factor Xa-inhibitor.^1,2,3

PER977 is a synthetic, small new molecular entity being developed by Perosphere that has been shown in pre-clinical studies to directly bind to heparins as well as circulating direct factor Xa- and IIa-inhibitors and therefore has the potential to reverse their anticoagulant effect.^4,5,6,7 PER977 does not bind to blood coagulation factors or other blood proteins.⁵ In pre-clinical studies, PER977 has demonstrated the ability to reverse the anticoagulant effects of direct factor Xa- and IIa-inhibitors in vitro and ex vivo in animal and human models.^4,6,7 PER977 reverses anticoagulant activity within 30 minutes after intravenous administration and has a clearance half-life of approximately 1.5 hours.⁵

“Novel oral anticoagulants were developed to help address the limitations of older anticoagulant agents, such as the need for frequent dose adjustments and monitoring,” said Jack Ansell, M.D., Professor of Medicine, NYU School of Medicine, and an advisor to Perosphere. “However, during severe bleeding or the need for emergency intervention, there is no established therapy to reverse the anticoagulant activity of these agents.”

Edoxaban is an investigational, oral, once-daily anticoagulant that specifically and reversibly inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting.^1,8 Edoxaban is currently approved only in Japan, since April 2011, for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, under the brand name Lixiana®.

Elsewhere, including Europe and the U.S., edoxaban is currently in phase 3 of clinical development and has not been approved. The global edoxaban clinical trial program includes two phase 3 clinical studies, Hokusai-VTE and ENGAGE AF-TIMI 48 (Effective aNticoaGulation with Factor XA Next GEneration in Atrial Fibrillation), which are evaluating edoxaban, administered once-daily, for treatment and prevention of recurrence of VTE in patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and for the prevention of stroke and systemic embolic events (SEE) in patients with non-valvular atrial fibrillation, respectively.^2,3

“Some potential reversal agents under evaluation for direct factor Xa- and IIa-inhibitors are recombinant proteins or fully humanized monoclonal antibody fragments,” stated Dr. Solomon S. Steiner, CEO of Perosphere. “PER977 is a synthetic agent that has the potential to be an antidote for both direct factor Xa- and IIa-inhibitors as well as heparins. In pre-clinical studies, PER977 has been shown to remain stable for more than one year.”

“The initiation of this study, in collaboration with Perosphere, is an important next step in the development of edoxaban,” said Mahmoud Ghazzi, M.D., Ph.D., Executive Vice President of Drug Development for the Americas and Chief Medical Advisor for Global Drug Development, Daiichi Sankyo. “Given our focus on optimizing patient care, the development of a reversal agent is a priority for Daiichi Sankyo in the event one may be needed by physicians.”

References

1. Ogata, K et al. Clinical Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Factor Xa Inhibitor Edoxaban in Healthy Volunteers. J Clin Pharmacol. 2010;50:743-753.
2. Clinicaltrials.gov: NCT00986154. Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots (The Edoxaban Hokusai-VTE Study). Available at: http://clinicaltrials.gov/show/NCT00986154. [Last accessed: April 2013].
3. Clinicaltrials.gov: NCT00781391. Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGEAFTIMI48). Available at: http://clinicaltrials.gov/show/NCT00781391. [Last accessed: April 2013].
4. Laulicht, B et al. Small Molecule Antidote for Anticoagulants. Circulation. 2012:126;A11395.
5. Perosphere Inc. Data on File.
6. Bakhru, S et al. Small Molecule Antidote for Anticoagulants. Presentation at the Thrombosis and Hemostasis Summit of North America, Chicago, Illinois, May 4, 2012. Available at http://www.perosphere.com/pdf/PER977-THSNA-Presentation_Slides.pdf. [Last accessed: April 2013].
7. Laulicht, B et al. Small Molecule Antidote for Anticoagulants. Presentation at the American Heart Association Meeting, Los Angeles, California, November 5, 2012. Available at: http://www.perosphere.com/pdf/PER977_AHA-presentation.pdf. [Last accessed: April 2013].
8. Comp, P. Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery. Pharmacotherapy. 2003;23(6):772-787.