• Product Pipeline
• Therapeutic Benefits of Aptamers
• ARC1779 in TMA/TTP
• ARC1779 in CEA

ARC1779 for TMA

Thrombotic microangiopathies, or TMA, is a group of rare blood disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, and microthrombi that occur primarily from the increase of vWF activity, which results in the formation of excessive blood clots which block, or occlude, the arterial circulation and cause injury to key organs, including the brain, heart and kidneys. This process leads to a consumption of platelets and thus a low platelet count and a variety of other symptoms such as anemia, purpura, renal failure, fragmented blood cells severed by fibrin products, and ischemic injury to target organs including the heart and brain. TMA include TTP and HUS. TTP has various forms, including familial TTP, which results from congenital defects or deficiencies of the enzyme ADAMTS13, which normally inactivates vWF; acquired or idiopathic TTP, which typically results from the formation of antibodies which inhibit the function of ADAMTS13; and forms of TTP which occur as a consequence of pre-existing medical conditions such as autoimmune disorders or drug toxicity related to procedures such as chemotherapy.

The enzyme ADAMTS13, which is responsible for regulating vWF by inactivating it, is necessary to maintain the normal balance between bleeding and clotting. In patients suffering from TMA, 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 TMA per million of the total population are diagnosed. There is no drug treatment specifically approved for patients with any form of TMA.

Role of von Willebrand Factor in TMA

When blood vessels are cut or damaged as a result of an injury, there is a natural process to stop the resulting loss of blood. This is accomplished by solidification of the blood during 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 platelet coating at the site of injury. Second, vWF plays an important role in the accretion of additional platelets, and stimulation of additional platelet functions strengthens and stabilizes the clot.

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 can bind many platelets at the site of an injury, the larger the multimer, the more extensive 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 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 multimers, 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 TMA, 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 episode in patients with TMA 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. In all forms of TMA, patients suffer from an increase of vWF activity, which leads to excessive platelet aggregation and clotting. However, the ADAMTS13 deficiency that characterizes TMA does not by itself trigger an acute episode in patients with TMA.

Patients with TMA may live for an extended period of time with normal platelet levels and an absence of the systemic blood clots that characterize an acute episode in patients with TMA. While there is no predictive method for determining when, or if, a TMA patient will suffer an acute episode, certain factors such as pregnancy, infections, or other conditions may increase this risk. Once patients have experienced an acute episode and recovered, they are considered to be in remission. While in remission, some of these patients are susceptible to a re-occurrence and may experience a subsequent acute episode. Based on published case studies, we believe that the risk of a recurrent episode ranges between 20% and 40% in patients with TTP.

Limitations of Current Therapies

There is no drug treatment specifically approved for patients with any form of TMA. Patients suffering from an acute episode of TTP are managed in the hospital by removing and replacing their plasma with fresh plasma from donors, which is known as plasma exchange. Although plasma exchange can reduce the risk of death, it is an expensive, invasive and time consuming procedure. Even with plasma exchange, acute episodes of TTP are associated with a high mortality rate, estimated to be as high as approximately 20%. Even in nonfatal cases there can be serious medical consequences such as strokes, seizures, kidney failure and heart attack. According to the Agency for Healthcare Research and Quality, or AHRQ, TTP patients require an average of nearly two weeks of plasma exchange therapy to achieve remission.

Potential Advantages of ARC1779

Because TMA 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 TMA. 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 TMA. We believe that treating patients suffering an acute episode of TMA 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, when we either added ARC1779 to blood samples taken from TTP patients or took blood samples from TTP patients treated with ARC1779, ARC1779 blocked excessive vWF activity and related platelet function.

Phase 1 Clinical Development

In March 2007, we completed a Phase 1 clinical trial of ARC1779 in 47 healthy volunteers. The primary objectives of the Phase 1 trial were to assess the safety and tolerability of ARC1779 and to establish proof of mechanism by determining the relationship between the administered doses of ARC1779 and the inhibition of plasma vWF activity and platelet function. The study evaluated five ascending doses of ARC1779, with each such dose administered as a single rapid infusion over approximately 15 minutes, and one additional dose of ARC1779 administered as a rapid infusion over approximately 15 minutes followed by four-hour infusion. Cutaneous bleeding time was measured as a proxy for bleeding risk potentially associated with ARC1779 administration. We observed no serious adverse events in the Phase 1 trial, however, one participant experienced an allergic-like reaction following a rapid bolus administration of ARC1779, resulting in dizziness, nausea, abdominal pain, shortness of breath, a flushing sensation, signs of hypotension, rapid heart rate, respiratory wheezing, and a few, diverse abnormal lab test results. No treatment intervention was required, and these signs and symptoms resolved spontaneously within 24 hours. In other participants, the occurrence of mild or moderately severe, non-serious adverse events which were potentially attributable to ARC1779 included dizziness, flushing, excessive sweating, chest discomfort, nausea, vein inflammation and a few, diverse abnormal lab test results.

We believe that the data from the Phase 1 clinical trial demonstrate the mechanism of action of ARC1779. ARC1779 demonstrated dose- and concentration-dependent inhibition of plasma vWF activity and platelet function. In the trial, we were able to inhibit both vWF activity and platelet function to the limits of assay detection.

In October 2007, prior to the commencement of our Phase 2a 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 for a total of 30 days. 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.

Phase 2a Clinical Development

Based on the results of laboratory experiments using blood extracted from TTP patients and our Phase 1 clinical trial of ARC1779 in healthy volunteers, we commenced a Phase 2a clinical trial of ARC1779 in January 2008. As of December 1, 2008, we had completed enrollment in the Phase 2a trial in TTP patients. This trial was conducted at a single center at the Medical University of Vienna in Austria and was designed to evaluate the safety and pharmacokinetic and pharmacodynamic activities of ARC1779 in patients with vWF-related platelet function disorders. Participants in the study included patients suffering an acute episode of TTP, patients who previously suffered an acute episode of TTP but are considered to be in remission, patients with familial TTP 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 included 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 TMA. We believe that studying the properties of ARC1779 in vWD-2B will generate supportive data for the continued clinical development of ARC1779 in TMA. We do not, however, intend to pursue ARC1779 for vWD-2B commercially.

The primary objective of the Phase 2a trial was to assess ARC1779’s activity in the presence of the excessive activity of vWF that characterizes TMA, as measured by changes in vWF activity, platelet count and vWF-related platelet function. We also evaluated the safety of ARC1779 in this trial. The Phase 2a trial enrolled 21 patients: three cohorts consisted of six total patients with TTP in remission; one cohort of eight patients who experienced an acute episode of TTP; one cohort of two patients with familial TTP who received ARC1779 administered both intravenously and sub-cutaneously; one cohort of two patients with vWD-2B; and one cohort of three patients with familial TTP who received a higher dose than that administered to the other cohorts in the Phase 2a trial. The TTP portion of the trial was open-label, while the vWD-2B cohort was randomized, double-blind and placebo-controlled. Each of the three cohorts of patients with TTP in remission received a different dose of ARC1779 over pre-specified dosing periods. We selected the three doses of ARC1779 tested in the Phase 2a trial based on the results of its Phase 1 clinical trial in healthy volunteers. Because each cohort is discrete, we can harvest and analyze data on a cohort-by-cohort basis. Initial data from the Phase 2a trial were presented at the American Society of Hematology meeting in San Francisco in December 2008. One poster presentation described the effects of ARC1779 on platelet counts in three patients suffering from TTP. This poster also disclosed data relating the concentration of ARC1779 to the platelet function and vWF activity. A second poster described the effects of administering ARC1779 to patients with vWD-2B.

In the Phase 2a clinical trial, we observed a serious adverse reaction. The reaction was an allergic-like reaction following administration of ARC1779, resulting in patient dizziness, nausea, abdominal pain, shortness of breath, a flushing sensation, abnormally low blood pressure, rapid heart rate, respiratory wheezing, and a few, diverse abnormal lab test results. A standard treatment protocol for presumed allergic reaction was administered and the patient fully recovered within a few hours with resolution of all clinical symptoms. In response and in order to lower the risk of such reactions in the future, we slowed the rate of administration, reducing the concentration and the rate of loading dose administration by means of a stepwise infusion in which the rate of administration and therefore the plasma concentration of ARC1779 rises slowly and incrementally. Because patients with TMA are already in the hospital for ongoing treatment a slower rate of administration is not problematic for patients with TMA.

Phase 2b Clinical Development

On August 4, 2008, we submitted an IND for the Phase 2b trial of ARC1779 to the FDA, which included interim safety data from the Phase 2a trial. The IND became effective on September 4, 2008. In September 2008, we submitted a request for a Clinical Trial Authorization, or CTA, to the United Kingdom and a Clinical Trial Application to Canada for this trial. Regulatory approval was granted in both countries in October 2008. In addition, we have submitted the necessary regulatory documents to the respective governing bodies overseeing the conduct of human clinical trials in Austria, Switzerland and Italy and are awaiting approval in these countries. Currently, one site in the United States is active and recruiting patients for the Phase 2b trial. We estimate that a total of approximately 35 sites worldwide will be activated and recruiting patients during the course of the Phase 2b trial. Assuming timely enrollment, we believe that the recruitment phase of the study could last approximately 24 months. Because TMA is a rare disease, the completion of the Phase 2b clinical trial will effectively be determined by the availability of patients to be recruited across the largest manageable number of study sites within a reasonable period of time.

The Phase 2b clinical trial is planned to evaluate the efficacy, safety and tolerability of ARC1779 in patients with TMA. In addition, we will observe the concentration response of ARC1779 for efficacy- and safety-related effects and the concentration response relationships among ARC1779 pharmacokinetic and pharmacodynamic parameters. The primary endpoint of the clinical trial is a composite of clinical events and biomarker evidence for injury to the target organs commonly affected by TMA, including the brain, heart, and kidneys. The Phase 2b clinical trial will be a randomized, double-blind, placebo-controlled, dose-ranging study in approximately 100 TMA patients. Enrolled patients will receive either one of three different doses of ARC1779 administered intravenously, or placebo. Treatment with ARC1779 or placebo is to be given in three ascending dose cohorts: a low dose cohort targeting a plasma drug concentration of 3 micrograms per milliliter, a medium dose cohort targeting a plasma drug concentration of 6 micrograms per milliliter and a high dose cohort targeting a plasma drug concentration of 12 micrograms per milliliter. The study is to enroll patients with initial or relapsed TMA including those with familial TTP, idiopathic acquired TTP, HUS or other related TMA.