Archemix : Products : ARC1779 in Thrombotic Thrombocytopenic Purpura

vWF is the Primary Mediator of TTP

Thrombotic thrombocytopenic purpura, or TTP, is a rare blood disorder that arises primarily from deficiency or inhibition of the enzyme ADAMTS13. This enzyme is responsible for breaking down vWF, and is necessary to maintain the normal balance between bleeding and clotting. In patients suffering from TTP, vWF is not properly broken down. This permits vWF to bind excessively to platelets, causing excessive blood clots. These clots form throughout the circulation and can lead to serious medical consequences such as strokes, seizures, kidney failure and heart attack. Each year in the United States, between four and 11 new cases of TTP per million of the total population are diagnosed. There is no approved drug treatment for patients with TTP.

Role of von Willebrand Factor in Thrombotic Thrombocytopenic Purpura

When blood vessels are cut or damaged as a result of an injury, the resulting loss of blood must be stopped before shock and possibly death occur. This is accomplished by solidification of the blood, a process called coagulation or clotting. When activated, vWF plays two important roles in the normal clotting process. First, vWF helps platelets adhere to damaged blood vessels. This immediate response forms an initial plug at the site of injury. Second, vWF plays an important role in the formation of fibrin, a tough mesh which strengthens and stabilizes the clot formed by the platelets. Specifically, vWF carries one of the clotting proteins to the site of injury.

An important part of the clotting process is the ability of vWF molecules to bind to one another to form larger molecules known as multimers. The size of these multimers allows them to bind to more platelets than a single vWF molecule. Because each multimer is able to bind to many platelets at the site of an injury, in general, the larger the multimer, the more effective the binding. However, if a vWF multimer becomes too large it can bind excessively to platelets and cause undesired clots. The size of vWF multimers is regulated by an important enzyme known as ADAMTS13, which breaks down vWF multimers that have become too large. In the absence of ADAMTS13, long chains of vWF molecules, known as ultra-large molecules, form. These ultra-large vWF molecules are especially adhesive and can bind excessively to platelets and cause undesired clots.

Although vWF is synthesized normally in patients suffering from TTP, the deficiency or inhibition of ADAMTS13 in these patients results in an abnormal persistence of ultra-large vWF molecules circulating in their blood. These circulating ultra-large molecules abnormally bind platelets together, causing widespread and excessive clot formation, or thrombosis. As these clots grow in size and multiply, they may result in an acute TTP episode that restricts blood flow to critical organs such as the brain, kidneys, and heart, which may potentially cause strokes, seizures, kidney failure or heart attack.

There are two forms of TTP, an inherited form and an acquired form. The inherited form is caused by mutations in the ADAMTS13 gene that impairs the normal function of ADAMTS13. Patients with the acquired form of TTP do not have mutations in this gene, but instead produce antibodies that block the activity of the ADAMTS13 enzyme. While most cases of TTP are acquired, both populations suffer from a deficiency of ADAMTS13 activity, resulting in excessive vWF activity, which leads to excessive platelet aggregation and clotting.

The ADAMTS13 deficiency that characterizes TTP does not by itself trigger an acute TTP episode. Patients with both the inherited and an acquired form of TTP may go for an extended period of time with normal platelet levels and an absence of the systemic blood clots that characterize an acute TTP episode. While there is no predictive method for determining when, or if, a TTP patient will suffer an acute TTP episode, certain factors such as pregnancy, infections, or other conditions may increase this risk. Once patients have experienced an acute TTP episode and recovered, they are considered to be in remission. While in remission, these patients are susceptible to a re-occurrence of an acute TTP episode. Based on published case studies, we believe that the risk of a recurrent TTP episode ranges between 20% and 40%.

Limitations of Current Therapies

There is no approved drug treatment for patients with TTP. Patients suffering from an acute episode are managed in the hospital by removing and replacing their plasma with fresh plasma from donors. Although plasma exchange can reduce the risk of death, it is an expensive and invasive procedure. Even with plasma exchange, acute episodes of TTP are associated with a high mortality rate, estimated to be as high as 20%. Even in non-fatal cases there can be serious medical consequences such as strokes, seizures, kidney failure and heart attack.

Potential Advantages of ARC1779

Because TTP is fundamentally a disease of excessive vWF activity, and because ARC1779 targets activated vWF, we believe that ARC1779 can reduce or eliminate the formation of blood clots that cause the morbidity and mortality associated with acute episodes of TTP.

We believe that ARC1779 can bind to and inhibit the activity of ultra-large vWF molecules, thereby potentially reducing the formation of blood clots in patients experiencing acute episodes of TTP. We believe that treating patients suffering an acute episode of TTP with ARC1779 in combination with plasma exchange could reduce the incidence of serious medical consequences such as strokes, seizures, kidney failure and heart attack. In laboratory experiments, we added ARC1779 to blood samples taken from TTP patients. These blood samples included blood drawn from two patients suffering an acute episode of TTP and eight patients in remission. The data showed that when ARC1779 was added to these blood samples, ARC1779 bound to the A1 domain of vWF and blocked excessive vWF activity and related platelet function.

Phase 2 Clinical Development

Based on the results of our laboratory experiments and our Phase 1 clinical trial of ARC1779 in healthy volunteers, we expect to commence a Phase 2 clinical trial of ARC1779 in January 2008. This trial, to be conducted at a single center at the Medical University of Vienna in Austria, is designed to evaluate the safety and pharmacokinetic and pharmacodynamic activity of ARC1779 in patients with vWF-related platelet function disorders. Participants in the study will include patients suffering an acute episode of TTP, patients who have previously suffered an acute episode of TTP but are considered to be in remission, and patients with a subtype of von Willebrand Disease, referred to as Type 2b, or vWD-2b, which is characterized by excessive, unregulated binding of vWF to platelets. We proposed the inclusion of patients with vWD-2b because the excessive, unregulated binding of vWF to platelets in these patients is similar to the binding of vWF to platelets in patients who suffer from TTP. We believe that studying the properties of ARC1779 in vWD-2b will generate supportive data for the continued clinical development of ARC1779 in TTP. However, we do not intend at this time to use this data to support separate clinical trials of ARC1779 in vWD-2b.

We expect to commence this Phase 2 clinical trial in January 2008. The primary objective of the Phase 2 trial is to assess ARC1779’s activity in the presence of the excessive activity of vWF that characterizes TTP, as measured by changes in vWF activity, platelet count and vWF-related platelet function. We also plan to further evaluate the safety of ARC1779 in this trial. Assuming we are able to initiate the trial as expected and enroll patients in a timely manner, we expect to complete this Phase 2 trial as soon as the third quarter of 2008.

We expect to have five cohorts of patients in this Phase 2 trial. Three cohorts of TTP patients will consist of patients with TTP in remission. The fourth TTP patient cohort will consist of patients who are experiencing an acute episode of TTP. The final cohort will consist of patients with vWD-2b. We plan to enroll up to four patients in each of the TTP cohorts, and up to 12 patients in the vWD-2b cohort. The TTP cohorts will be open-label, while the vWD-2b cohort will be randomized, double-blind and placebo-controlled. Each of the three cohorts of patients with TTP in remission will receive a different dose level of ARC1779 over pre- specified dosing periods. We have selected the three doses of ARC1779 to be tested in the Phase 2 trial based on the results of our Phase 1 clinical trial in healthy volunteers.

In October 2007, prior to the commencement of our Phase 2 clinical trial, a physician at the Medical University of Vienna in Austria administered ARC1779 to a patient diagnosed with acute TTP. In Europe, medical practitioners can request and use certain product candidates prior to their approval by the applicable regulatory authorities where there is unmet clinical need and the practitioners are satisfied that the use of the product candidate would provide a direct benefit to the patient. This practice is referred to as treatment on a named patient basis.

ARC1779 was administered in conjunction with daily plasma exchange to this TTP patient beginning on October 27, 2007. The final course of ARC1779 was administered on November 19, 2007. During this course of treatment, we observed a sustained rise in the patient’s platelet count and a reduction in the levels of biomarkers associated with cellular damage in the circulatory system. We believe these data demonstrate that ARC1779 interfered with the disease process, reducing the excessive vWF activity and resulting platelet aggregation that is the hallmark of acute TTP. Notwithstanding the results observed in this single patient, we may not be able to replicate these results in our Phase 2 clinical trial of ARC1779 in TTP patients.

We believe that ARC1779 for treatment of acute episodes of TTP meets the criteria for orphan medicinal product designation in the European Union and orphan drug designation in the United States. We intend to seek orphan designation for ARC1779 for the treatment of acute episodes of TTP. If we receive orphan designation for ARC1779 in TTP from the EMEA, we then intend to seek agreement with the EMEA on the future clinical trials needed for registration in the European Union of ARC1779 for treatment of acute episodes of TTP. We also intend to request orphan designation from the FDA and to seek agreement with the FDA on the future clinical trials needed for registration of ARC1779 for treatment of acute episodes of TTP in the United States.