How much is NAPc2 worth after successful (???) first phase of the PII trial? We know how much is worth without. Is Lampert just fishing for better conversion price? Is DNA moving forward with anti-TF-antibody?
From 10K:
rNAPc2
Recombinant nematode anticoagulant protein c2, or rNAPc2, is a novel and potent anticoagulant in clinical development for the prevention and treatment of acute coronary syndromes, which include unstable angina, or UA, and non-ST-segment elevation myocardial infarction, or NSTEMI. We originally discovered NAPc2, a natural form of the protein, in blood-feeding hookworms. rNAPc2 has been evaluated in over 500 patients and healthy volunteers in several Phase I studies, Phase II trials for the prevention of deep vein thrombosis, or DVT, and pulmonary embolism, as well as a Phase IIa safety trial in low-risk patients undergoing elective percutaneous coronary intervention, or PCI. Since many UA/NSTEMI patients receive medical intervention to open up clogged arteries, we conducted this study to determine the safety of rNAPc2 in such circumstances. The data showed that rNAPc2 appears to be safe and well tolerated in this patient population. Based upon this safety data, in November 2002, we initiated a Phase II clinical program in UA/NSTEMI patients.
Abnormal blood clot formation, or thrombosis, can reduce or completely block the flow of blood and oxygen supply to vital organs, which can lead to serious clinical conditions. The formation of blood clots in one or more coronary arteries of the heart may result in UA/NSTEMI, which oftentimes progresses to myocardial infarction, or heart attack, if left untreated. UA and NSTEMI are characterized by severe chest pain, even at rest, often the result of clogged coronary arteries.
Blood clot formation is a normal repair mechanism that the body uses to recover from damage to blood vessels resulting from cuts, bruises or disease. The formation of a blood clot results from a complex series of biochemical events known as the blood coagulation cascade, which involves enzymes called serine proteases, cellular fragments called platelets and other proteins in blood.
The coagulation cascade is most often triggered when there is damage or disruption to the lining of the blood vessel wall, or endothelium. This damage or disruption exposes the protein Tissue Factor, or TF, to the blood, allowing the serine protease Factor VIIa, which circulates freely in the blood, to bind to TF. The resulting Factor VIIa/Tissue Factor complex, or FVIIa/TF, is the initial trigger of the coagulation cascade and promotes the formation of another serine protease Factor Xa. Factor Xa causes the formation of the key serine protease thrombin. Thrombin then cleaves the protein fibrinogen into fibrin and activates platelets in the blood, which stick to each other and to the fibrin matrix, to form a blood clot in the damaged blood vessel. The resulting blood clot blocks blood flow and oxygen delivery to heart tissues, causing severe chest pain.
The blood coagulation cascade is characterized by exponential amplification, starting with a small number of FVIIa/TF complexes and culminating in the formation of millions of thrombin molecules. Recombinant NAPc2 inhibits FVIIa/TF, thereby preventing the formation of thrombin. We believe that inhibiting the relatively few FVIIa/TF complexes early in the cascade may have significant safety and efficacy advantages over other anticoagulant strategies including indirect thrombin inhibitors such as unfractionated heparins and low molecular weight heparins, or LMWH, as well as direct thrombin inhibitors such as Angiomax, all of which target thrombin late in the cascade after amplification has occurred.
Results from our Phase II open-label dose-ranging trial in 292 patients undergoing elective unilateral knee replacement surgery demonstrated that rNAPc2 appeared to reduce the risk of developing DVT and related complications by greater than 50% compared to the current standard therapy of unfractionated LMWH without compromising safety. Based on an end-of-Phase II meeting and subsequent communications with the Food and Drug Administration, or FDA, we concluded that an additional Phase II trial for DVT would be required to firmly establish a more commercially viable fixed dosing regimen. Although we continue to believe that rNAPc2 is a safe and effective therapy for the prevention of DVT, we made a decision in October 2001 to focus the clinical development of rNAPc2 on unstable coronary syndromes, which we believe is more commercially viable based on both the time to market and the rapidly-changing commercial environment in the DVT prophylaxis arena. Future clinical development of rNAPc2 in DVT will depend on securing an appropriate development partner.
MARKET OPPORTUNITY. It is estimated that there are over 1.4 million hospitalizations for UA/NSTEMI each year in the United States alone. Historically, UA/NSTEMI has been treated with aspirin plus LMWH or unfractionated heparin. Recent guidelines have recommended that nearly all patients receive the antiplatelet agent Plavix in addition to the historical standard of care. We are developing rNAPc2 to be added to the current standard of care therapies. In moderate to high-risk patients with severe coronary artery disease, UA/NSTEMI may be treated with interventions such as PCI, which includes percutaneous transluminal coronary angioplasty, or PTCA, and stent placement.
Patients may also undergo coronary arterial bypass grafting or bypass surgery. In some cases, these patients may then receive antiplatelet drugs such as glycoprotein IIb/IIIa antagonists like ReoPro, Integrelin or Aggrastat. Traditional therapies are not completely effective; it is estimated that 8-15% of UA/NSTEMI patients will require additional PCI, suffer a heart attack or chest pain, or die within 30 days of hospital admission despite treatment with the current standard and use of an early interventional approach. By blocking the first step in the formation of a blood clot, we believe rNAPc2 may afford significant clinical benefit in high-risk patients with UA/NSTEMI when administered in combination with LMWH and aspirin, which work at later steps of the coagulation cascade.
DEVELOPMENT STATUS. In order to establish the safety of rNAPc2 prior to initiating clinical trials in patients with unstable angina, we completed a double-blinded, placebo-controlled, dose-ranging Phase IIa study in patients undergoing elective PCI. In this trial, patients were randomized to receive either rNAPc2 or placebo with unfractionated heparin, aspirin and, in most cases, Plavix. The primary goal of the study was to assess safety as measured by femoral, or groin, compression time, which is a measure of the extent of bleeding at the surgical site used for placement of the coronary catheter. The Phase IIa results indicate that rNAPc2 appears to be safe and well tolerated in this patient population and that, in contrast to standard therapy with unfractioned heparin, aspirin and Plavix alone, rNAPc2 was shown to be more effective in suppressing the formation of thrombin in this elective PCI patient population.
Based on the safety data obtained in this Phase IIa trial, in November 2002 we initiated a double-blinded, placebo-controlled Phase II clinical program of rNAPc2 in unstable angina patients. This trial, referred to as the Anticoagulation with NAPc2 To Help Eliminate MACE (ANTHEM/TIMI-32), is being coordinated with the help of the Thrombolysis in Myocardial Infarction, or TIMI, Group led by Dr. Eugene Braunwald of Brigham and Women's Hospital and Harvard Medical School. The TIMI Group has been performing clinical research in patients suffering from acute coronary syndromes since 1984. The ANTHEM/TIMI-32 Phase II program is composed of three parts. We will have an opportunity to decide whether to proceed with the trial following the conclusion of each part based on an evaluation of safety and efficacy. The first part, which is ongoing, is a double-blinded, randomized, placebo-controlled, dose-ranging trial which is designed to determine the safety of intravenously administered rNAPc2 in moderate to high-risk UA/NSTEMI patients undergoing PCI. This part is intended to sequentially enroll 125 patients at clinical centers in the United States randomized to either placebo or one of five rNAPc2 dose groups starting at 1.5 micrograms per kilogram of body weight increasing to 5.0 micrograms per kilogram. All patients will receive the low molecular weight heparin enoxaparin, or Lovenox, and aspirin, with the use of glycoprotein IIb/IIIa antagonists and Plavix determined by the attending physician. The primary objective of this portion of the trial is to determine a safe dose range for rNAPc2 in these patients using established and accepted criteria for bleeding. During the first part of this program, we will measure efficacy by the incidence of ischemic events as determined from seven day continuous electrocardiographic monitoring using portable Holter devices.
The second and third parts of the ANTHEM/TIMI-32 program, which will follow the first part assuming favorable clinical results, are intended to focus on a broader patient population in both North America and Europe and will include moderate to high-risk patients that are not subject to an early interventional treatment strategy such as PCI. The primary efficacy endpoint for these subsequent phases of the clinical program are planned to be ischemic events measured using Holter monitors and clinical events including death, myocardial infarction and recurrent ischemia requiring re-hospitalization. This entire clinical program, which is expected to enroll 1,525 patients, is scheduled to take 18-24 months to complete. |
