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A Novel Oral Anticoagulant is Planned to be Developed for Patients with
Prosthetic Heart Valves or Chronic Renal Dysfunction
SUNNYVALE, CA - MARCH 8, 2013. Armetheon, Inc., a clinical stage biopharmaceutical company,
announced today that it plans to develop its novel oral anti-coagulant (OAC), tecarfarin (ATI-5923), for a
patient population which includes those who have prosthetic heart valves or chronic renal dysfunction. In
these patients, currently available OACs are contra-indicated or inadequate. Tecarfarin, a potentially best-in-
class OAC, was designed to avoid cytochrome P450 (CYP) related metabolism that is a major cause of safety
and efficacy problems related to the use of warfarin (Coumadin®), the current standard of care. In a recently
completed phase 3 pivotal clinical trial (EMBRACE-AC), tecarfarin was shown to be safe and effective as an
OAC in patients with prosthetic heart valves in addition to those with other conditions such as atrial
fibrillation or venous thromboembolism, independent of their CYP status. 
“Anti-coagulation is challenging in patients with prosthetic heart valves, where non-monitored oral anti-
coagulation therapies are not indicated, and where a safe and effective alternative to warfarin would address
an important clinical burden,” commented Lord Ajay Kakkar, Professor of Surgery, University College
London, England.
In December 2012, following a number of fatalities, the FDA informed health care professionals and the
public that the novel non-monitored OAC which directly inhibits thrombin should not be used in patients
with mechanical heart valves. Experts now recommend that none of the novel non-monitored OACs be used
in patients with any type of prosthetic valves. 
One of the major causes of unpredictable variability in warfarin anticoagulation response leading to bleeding
complications or stroke is its metabolism by the enzyme, CYP2C9. This variability is further exacerbated if
patients have a genetic variant of this enzyme. 
“Tecarfarin was specifically designed not to be metabolized by any CYP enzymes, which means it may
require less monitoring than warfarin. Some monitoring, according to experts, may still be needed to ensure
patient compliance. Data from EMBRACE-AC trial showed that tecarfarin is a more effective OAC than
warfarin in patients with a CYP2C9 genetic variant taking at least one CYP2C9 inhibitor despite close
monitoring, ” said Dr Peter Milner, Executive Chairman of Armetheon and partner at AshHill
Pharmaceutical Investments. He added, “for approval of tecarfarin, we anticipate only one more pivotal
clinical trial will be required which could be a ‘real world,’ open label study involving about 2500 pre-
defined patients”. 
Recent research indicates that patients with chronic renal dysfunction or failure have reduced or variable
activity of CYP enzymes such as CYP2C9 and CYP3A4 as well as the transporter permeability glycoprotein
(P-gp). This may explain warfarin’s suboptimal performance in this patient population. Currently marketed
novel non-monitored OACs (in particular, Factor Xa inhibitors) are eliminated via the kidney and most of
them are metabolized via CYP3A4 enzymes in addition to interacting with the P-gp. This may explain the
significant variability in anticoagulation response to the novel non-monitored OACs in patients with chronic
renal dysfunction or failure. 
“Genetic and other sources of variability in the drug metabolizing enzymes CYP3A4 and CYP2C9 or
transport related proteins such a P-gp could lead to unpredictable variability in plasma levels of drugs that are
metabolized/eliminated through these pathways, particularly if they are used with concomitant medications
that may be inhibitors of these metabolic/elimination pathways,” said Professor Leslie Z. Benet, former
Chairman and Professor of Biopharmaceutical Sciences at University of California San Francisco (UCSF), a
world-renowned expert in pharmacokinetics, CYP-dependent drug metabolism and P-gp dependent drug
Unlike many of the novel non-monitored OACs and warfarin, tecarfarin is not metabolized by CYP enzymes
or transported by P-gp in addition to not being excreted via the kidney. 
“For oral anticoagulation, we believe tecarfarin if approved will be an important clinical tool in addition to
warfarin and the novel non-monitored OACs. We are preparing to meet with the FDA and the EMA to
propose a clinical trial design and final registration package for tecarfarin in these two regions,” said Dr M.
(Ken) Kengatharan, President & COO of Armetheon and a General Partner at Atheneos Capital. He added,
“we expect to submit for marketing authorization in the US and the EU in less than 4 years. With an
increasing use of CYP variant genetic testing and the recent uptick in patient self-monitoring perhaps due to
reimbursement by healthcare providers, we strongly believe the time to develop and commercialize
tecarfarin is now”. 
About anti-coagulation therapy in special populations 
Oral anticoagulants, are used to slow down or stop the formation of blood clots in the out-patient
environment. Currently available anticoagulants include warfarin (Coumadin®) that inhibits vitamin K
epoxide (VKOR) and the novel non-monitored OACs that directly either inhibit thrombin or Factor Xa. In
patients with prosthetic heart valves, OACs are given to prevent clot formation within these valves. Patients
with mechanical heart valves generally remain on warfarin sometimes in combination with aspirin while
most patients with bioprosthetic valves are eventually switched to aspirin. However, experts now recommend
that the novel non-monitored OACs should not to be used in these patients.  
In patients, who have a genetic variant of metabolizing enzymes such as CYP2C9, anticoagulation therapy is
difficult to manage well, even if closely monitored, particularly if they take medicines or foods that affect
these enzymes. Recent data shows that these drug metabolizing enzymes are down regulated in patients with
chronic renal dysfunction or failure which may explain the sub-optimal anti-coagulation control with
warfarin or with the novel non-monitored OACs in these patients. 
Monitoring the effectiveness of warfarin in many cases requires patients to travel frequently to a local clinic
to have their anticoagulation status checked and, if needed, doses adjusted. Recently, perhaps due to
reimbursement by healthcare providers, there has been an increase in patient self-monitoring and
management of anticoagulation therapy that is currently only applicable to VKOR inhibitors such as
tecarfarin. Ultimately, this system could provide many patients with a cost-effective management of
anticoagulation therapy with a better patient compliance than with new oral non-monitored OACs. 
About Tecarfarin 
Tecarfarin (ATI-5923) is potentially a best-in-class orally active vitamin K epoxide (VKOR) inhibitor that
was specifically designed to avoid CYP2C9 dependent metabolism and to avoid transport by P-gp. This may
mean tecarfarin will need less monitoring than warfarin, potentially resulting in better patient compliance if
used together with widely available self-monitoring systems. Unlike the novel non-monitored OACs,
tecarfarin has an antidote, vitamin K that is readily available and can be used to rapidly reverse the
anticoagulation effect of tecarfarin in an emergency. If approved, tecarfarin could become a superior
anticoagulation management solution to warfarin.  
About Armetheon 
Armetheon, Inc. is a privately held San Francisco Bay area based clinical stage biopharmaceutical company
focused on the development of novel drugs for highly unmet need. The company has 3 programs in mid - to
late - clinical stage development. Armetheon’s current investors include AshHill Pharmaceutical Investments
and Atheneos Capital. For more information: 
M. (Ken) Kengatharan, Ph.D., M.B.A., President & COO Office +1 650 646 3898 + ext 101 mkengatharan(at)



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