Novel Oral Anticoagulant is Planned to be Developed for Patients with
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
“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,
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
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 of 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 transport.
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.
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.
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: http://www.armetheon.com
M. (Ken) Kengatharan, Ph.D., M.B.A.,
President & COO
Office +1 650 646 3898 + ext 101
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