Zemiva (Iodofiltic Acid I-123; BMIPP) is Molecular Insight’s lead molecular imaging radiopharmaceutical product candidate under development for the diagnosis of myocardial ischemia, including acute coronary syndrome (ACS), both due to insufficient blood flow to the heart muscle, including myocardial infarction, or heart attack (heart muscle death). The initial target market for Zemiva is for the rapid diagnosis of myocardial ischemia or heart attack in the emergency department setting in chest pain patients, many of whom have an uncertain diagnosis after initial evaluation. The ability to more rapidly and accurately detect cardiac ischemia will lead to improved patient outcomes by allowing more timely intervention. The ability to rule out myocardial ischemia allows doctors to send patients home safely, thereby reducing unnecessary admissions and/or additional medical procedures, and the associated costs and risks. Zemiva imaging can be adopted on a widespread basis since every accredited hospital in the United States has nuclear medicine imaging capabilities that allow for quality Zemiva imaging. Additional patient populations that would benefit from Zemiva include those with: end-stage renal disease, acute decompensated heart failure, diabetes, and microvascular atherosclerosis, a common presentation of myocardial ischemia, especially in women.
The heavy work load of the heart requires large amounts of energy to function properly. The heart obtains the majority of its energy by burning fatty acids as its major fuel. In order to metabolize fatty acids efficiently, the heart must have a sufficient supply of oxygen. If the oxygen supply is limited, the heart shifts from the metabolism of fatty acids to the metabolism of carbohydrates. In this way, the cells of the heart maintain viability by burning a fuel that requires less oxygen.
The role of cardiac metabolic imaging for the visualization of cardiac ischemia can be explained in simple terms as a see-saw: on one side is fatty acid metabolism and on the other side, carbohydrate metabolism. Fatty acids are the dominant fuel used by the healthy heart and when oxygen is in sufficient supply. When oxygen supply is insufficient (coronary atherosclerosis or coronary artery disease – CAD) or there is an oxygen supply/demand mismatch, as in the case of myocardial ischemia, the see-saw tips in favor of carbohydrate metabolism, a fuel that can be metabolized in the presence of much lower levels of oxygen. Unlike a conventional see-saw that easily pivots back and forth, myocardial metabolism is different. Myocardial ischemia creates a rapid swing away from fatty acid metabolism over to carbohydrate metabolism. But the metabolic see-saw doesn’t rapidly swing back after an ischemic event, even if blood flow is restored or normalized. This prolonged period of reduced fatty acid metabolism has been referred to as “ischemic memory,” an alteration in fatty acid metabolism that can be visualized using Zemiva for as many as 30 hours after an ischemic event has taken place.
Zemiva is an iodine 123-labeled branched chain fatty acid analog, delivered by an intravenous injection. Zemiva is retained in heart cells that have a healthy blood supply but not retained in ischemic heart cells. Because of its high uptake and long retention in healthy heart cells, Zemiva provides high-quality images of the heart.
Sustained decrease in fatty acid metabolism allows Zemiva to visualize an ischemic event for up to 30 hours after it has occurred. This was demonstrated in the Molecular Insight Phase 2a study that was published in the journal Circulation in 2005. Ischemic memory is a unique capability of Zemiva and makes it valuable for imaging in the acute setting, when stress testing cannot be tolerated, and in patients whose symptoms have since subsided.
The Market Opportunity
In the United States, approximately six million people visit the emergency department each year complaining of chest pain. Some of these patients will have initial testing performed that clearly indicates the patient is having a heart attack; however the majority will not have definitive test results, resulting in an indeterminate or equivocal diagnosis. This lack of diagnostic certainty means a delay in proper patient management, and for those with myocardial ischemia, identifying those who need immediate care. This delay in diagnosis in the current standard of care for the acute chest pain patient drives a conservative medical approach leading to a large number of hospital admissions for prolonged observation. This results in three million hospital admissions for non-cardiac chest pain patients; a low-risk patient population that could be safely discharged if more rapid and reliable diagnostic techniques were available. The healthcare costs associated with these admissions is greater than $6 billion in the United States alone.
The additional three million equivocal patients cannot be diagnosed immediately and are admitted to the hospital for observation and further testing, often spending up to three days undergoing a lengthy and expensive series of diagnostic tests, including a stress test after the patient has been stabilized. In the end, only 15 percent of equivocal patients are ultimately diagnosed with cardiac disease while the other 85 percent have another medical or no medical condition. This inability to quickly diagnose patients results in unnecessary medical costs of more than $6 billion each year.
Diagram: 6 Million Patients Present with Chest Pain
Zemiva may provide the opportunity to improve disease management by allowing the rapid and more accurate diagnosis of patients with cardiac conditions, minimizing the number of potentially life-threatening, missed diagnoses among discharged patients and reducing hospitalization costs by quickly ruling out patients with conditions not related to ischemia.
Currently available molecular imaging compounds are highly time sensitive and considered effective only when used during ongoing symptoms. Zemiva enables the detection of cardiac ischemia, without a stress test for up to 30 hours following an ischemic episode. With an expanded “imaging window,” Zemiva could enable more timely, convenient and cost-effective diagnosis of cardiac ischemia compared to the current standard of care.
Diagram: 3.5 Million Equivocal Patients with Chest Pain
Clinical Development Plan
To date, over 800 subjects have received Zemiva in Molecular Insight’s five human clinical trials (one Phase 1 and four Phase 2 trials). The most recently completed Phase 2 clinical study (BP-23) showed that Zemiva, when combined with the standard of care for the diagnostic evaluation of a chest pain patient, significantly improves the detection of cardiac ischemia when compared to the standard of care alone. In the trial, the combination of Zemiva imaging with initial clinical diagnostic information resulted in improved sensitivity for detecting ischemia (85%) that was statistically significant when compared to the sensitivity of the initial clinical diagnosis alone (52%). The improved sensitivity was evident even in patients whose chest pain symptoms had subsided up to 30 hours prior to the Zemiva scan. These results were consistent for the subset of patients with acute coronary syndrome (ACS), the most severe form of myocardial ischemia. In both cases, sensitivity and negative predictive value were improved while specificity was maintained. In patients with a negative Zemiva scan, there were no heart attacks or deaths from cardiac causes during the 30-day follow up period.
The BP-23 trial enrolled 510 patients over 14 months at 50 hospitals throughout North America. The primary objective was to evaluate the ability of Zemiva to identify myocardial ischemia in patients presented at the emergency department with suspected ACS. The primary endpoint of the trial was to determine the performance (sensitivity and specificity) of Zemiva and the key secondary endpoint was to determine the clinical benefit of the use of Zemiva as a complement to the current standard of care. The trial met both the primary and key secondary endpoints. Zemiva was well tolerated. There were no serious adverse effects associated with the product and no patients discontinued the product due to adverse events. With the successful BP-23 results, the Phase 2 clinical development requirements have been met and Molecular Insight will proceed to Phase 3. FDA has indicated that a single Phase 3 trial, with robust results, would be sufficient to support Zemiva’s approval. The Phase 3 trial will begin in 2010.