Molecular Insight Pharmaceuticals, Inc. (NASDAQ: MIPI) announced that the European Medicines Agency (EMEA) has approved its Phase 3 protocol for Onalta (Yttrium-90 edotreotide). Onalta is the Company’s lead radiotherapeutic product candidate under development for the treatment of metastatic carcinoid and pancreatic neuroendocrine tumors in patients whose symptoms are not controlled by conventional therapy. The compound has shown the potential to selectively deliver lethal radiation to cancer cells. The proposed Phase 3 trial will confirm that administration of Onalta results in stabilization, regression or complete remission of the carcinoid tumor, and improves carcinoid-related symptoms when compared to a high-dose regimen of the current standard therapy for this disease, Sandostatin®. With EMEA’s approval of its proposed Phase 3 protocol in hand, Molecular Insight can proceed with the final clinical trial that will position Onalta for marketing authorization in the EU.

EMEA notified Molecular Insight that its Onalta Phase 3 protocol is acceptable, including the plan to assess and manage renal tolerance, that the endpoints and measures are appropriate, and that the number of patients proposed to be presented in support of safety for the future Marketing Authorization Application (MAA) is acceptable.

John W. Babich, Ph.D., Executive Vice President, Chief Scientific Officer and President of Research and Development of Molecular Insight, said that, “This is a significant Company milestone that allows us to proceed with a pivotal trial for Onalta in Europe. A successful trial would mean an innovative and well-understood therapy could be made available to thousands of patients whose lives are being cut short and who suffer from the debilitating symptoms that accompany this disease.

“The notification by EMEA comes on the heels of our Special Protocol Assessment (SPA) agreement with FDA allowing us to proceed to a pivotal phase 2 trial for Azedra™ Ultratrace™ (Iobenguane I-131) in another neuroendocrine cancer, pheochromocytoma. Azedra is also currently being evaluated for treatment of neuroblastoma. These drug candidates represent significant opportunities to provide neuroendocrine cancer patients with innovative therapies. Molecular Insight has selected Progression Free Survival (PFS) as the primary endpoint for the proposed Phase 3 study and overall survival will be assessed as a key secondary endpoint. The regulatory progress in Europe will hopefully be followed by regulatory progress in the USA.”

According to Dr. Val Lewington, Consultant Physician, Royal Mardsen NHS Foundation Trust, “EMEA approval of this Phase 3 protocol represents a landmark in radionuclide therapy. The potential of this approach is well-recognized in Europe but this will be the first opportunity to evaluate this peptide-based radiotherapy in a major, multi-center, randomized clinical trial. It is difficult to overstate the importance of this step in the development of innovative therapies for inoperable neuroendocrine tumors which so often prove refractory to other treatment options. News of the EMEA decision will be welcomed enthusiastically both by clinicians and by patients with neuroendocrine disease.”

The proposed Phase 3 protocol will evaluate 194 patients with metastatic, progressive, somatostatin receptor-positive, carcinoid cancer, receiving either Onalta or the standard of care. Carcinoid cancer is a rare, serious and life-threatening condition that affects a group of patients with few treatment options. Once the disease has metastasized, the patients’ prognosis is poor: the best five-year survival rate is reported to be 20 - 30 percent.

Onalta is intended to complement Azedra™, Molecular Insight’s other clinical stage radiotherapeutic candidate for the treatment of neuroendocrine tumors. In 2007, Molecular Insight acquired Onalta from Novartis Pharma AG, which had conducted three Phase 1 and three Phase 2 clinical trials involving more than 300 patients.

About Onalta

Molecular Insight has been developing Onalta as a treatment for metastatic pancreatic neuroendocrine and carcinoid tumors in patients whose symptoms are not controlled by current somatostatin analogue therapy. Neuroendocrine tumors are a type of cancer that arises from neuroendocrine cells and can occur in different parts of the body. A somatostatin analogue is a synthetic compound, in this case a peptide, which functions in the body in a manner similar to the hormone somatostatin, which regulates a variety of other metabolic hormonal functions. Onalta binds selectively to tumor cells that have receptors for the peptide hormone somatostatin on their surface and serves as a carrier for targeted delivery of a lethal dose of radiation to the cancer cells through the radioactive decay of yttrium-90. The compound has been used to treat patients in Europe on an investigative basis for more than 10 years. There are no approved treatments in the U.S. for metastatic neuroendocrine tumors.

Source
Molecular Insight Pharmaceuticals, Inc.

BOSTON, May 18 — Safe extraction of pacemaker and implantable defibrillator leads is not a task for tyros — it requires a minimum of 40 extractions under the supervision of a fully-qualified training physician, according to a consensus statement released by the Heart Rhythm Society.

• Explain to interested patients that this report describes a consensus statement issued by a professional organization, whose members are electrophysiologists.

Moreover, once a physician has been trained in proper technique, he or she should perform a minimum of 20 extractions a year to maintain skills at a safe level, said Bruce Wilkoff, M.D., director of cardiac pacing and tachyarrhythmia devices at the Cleveland Clinic Foundation and a vice president of the Heart Rhythm Society.

The bar defining “fully-qualified training physician” was also set high: he or she must have performed at least 75 extractions as the lead operator and must have a safety and efficacy record at least as good as published norms.

Dr. Wilkoff said that “more than 80% of the panel’s time was spent on discussion of indications for lead extraction.”

The lengthy discussion indicates the difficulty in evaluating risks versus benefits of what is “an invasive procedure,” Dr. Wilkoff said.

The statement made recommendations for four specific indications — infection, chronic pain, thrombosis or venous stenosis, and “leads that are no longer clinically useful.”

According to the statement, both the device and the lead should be removed “in all patients with definite [cardiovascular implantable electronic device] system infection as evidenced by valvular endocarditis, lead endocarditis, or sepsis.”

Likewise, both the device and the leads should be removed in patients with “occult gram positive bacteremia (not contaminant) device pocket infection and in patients “with valvular endorcarditis without definite involvement of the leads and/or device.”

Device and lead removal are not, however, indicated for “a superficial or incisional infection without involvement of the device and/or leads,” nor is removal recommended to treat chronic bacteremia when the source is not the device or leads.

When chronic pain is the complaint, device removal is considered reasonable when pain at the device or lead insertion site is not manageable by medical or surgical techniques.

Device and lead removal is recommended for thrombosis or venous stenosis but the level of evidence is weaker than the evidence in support of removing devices when infection is present.

In most cases, the panel recommended removal for nonfunctioning leads, but said removal is not necessary in patients who have a life expectancy of less than a year.

The panel listed a series of scenarios in which functional leads should be removed, including “patients with life threatening arrhythmias secondary to retained leads,” or when device design or device failure “may pose an immediate threat to the patients if left in place (e.g., Teletronics ACCUFIX J wire fracture with protrusion).”

The panel also recommended removal of functional leads when the leads interfere with cancer treatment.

Dr. Wilkoff has disclosed that he has received grant/research support from Medtronic, St. Jude Medical, Boston Scientific, Spectranetics, and Biotronik. He is a consultant for Medtronic, St. Jude Medical, Boston Scientific, Spectranetics, Cook, and LifeWatch.

Primary source: Heart Rhythm Society

Source reference:
Wilkoff BL, et al “Transvenous lead extraction: heart rhythm society expert consensus on facilities, training, indications, and patient management” HRS 2009; in press (Heart Rhythm, July 2009).

St. Jude Medical, Inc. (NYSE:STJ) announced the results from the Substrate versus Trigger Ablation for Reduction of Atrial Fibrillation (STAR-AF) trial. The findings were presented during a late-breaking clinical trials session at Heart Rhythm 2009, the annual Heart Rhythm Society’s Scientific Sessions in Boston.

The STAR-AF trial, sponsored by St. Jude Medical, was an open, randomized, prospective, multicenter clinical trial involving 108 patients, administered in several Canadian and European centers. Designed as a three arm trial, it compared the generally accepted treatment approach of pulmonary vein isolation (PVI), with complex fractionated electrogram (CFE) guided therapy, and with a third arm that combined the two therapies. The primary endpoint of the trial was relief of atrial fibrillation (AF) episodes of 30 seconds duration or greater, up to 12 months after treatment.

Study results indicate that after one ablation procedure, a combination of PVI and CFE guided therapy demonstrated significantly higher freedom from AF, at 74 percent, as compared to PVI alone at 47 percent and CFE guided therapy alone at 29 percent. Importantly, 94 percent of patients who received the combination of these treatments remained off any anti-arrhythmic medications at the end of the 12-month follow-up period.

Atrial fibrillation is a condition in which the upper chambers of the heart (atria) beat rapidly and erratically, affecting the heart’s ability to adequately pump blood to its lower chambers (ventricles) and subsequently to the rest of the body. The STAR-AF trial studied patients with both symptomatic high burden paroxysmal (intermittent, but frequent and prolonged AF) and those with persistent AF. These two groups represent the largest subset of patients with AF; they experience varying degrees of intermittent AF episodes. The study participants had been unresponsive to medication that is meant to alleviate symptoms or the abnormal heart rhythm itself.

“While many unanswered questions remain about the origins of and best treatment options for AF, the results of STAR-AF indicate that perhaps traditional pathways are not the optimal ones. By mapping for the areas of CFE during AF ablation, we have demonstrated an incremental benefit for patients who historically may have undergone only a PVI,” said Atul Verma, M.D., an electrophysiologist in the Heart Rhythm Program at Southlake Regional Health Centre in Newmarket, Ontario, Canada, who was the principal investigator in the study. “Moreover, I feel that using an automated method for identifying the areas of CFE removes some of the subjectivity that exists in accurately targeting those regions of interest, and may be useful to physicians as they perform AF ablation.”

CFEs are highly random and chaotic electrical signals in the atria that may be a source of origin or perpetuation of AF - they are extremely difficult to identify accurately by visual inspection alone. Therefore, an automatic algorithm from St. Jude Medical’s EnSite™ System was used to identify these regions in the patients randomized to receive this treatment course. The CFE guided therapy alone and hybrid PVI and CFE guided therapy strategies were being studied because often a PVI alone will result in either recurrence of AF or another complicated atrial rhythm that requires additional patient intervention.

“The results of the STAR-AF trial represent an important step toward understanding the best set of tools and therapies for treating cardiac arrhythmias, such as AF, and highlights St. Jude Medical’s commitment to providing pioneering research to improve treatment of this condition,” said Denis Gestin, president of the St. Jude Medical International Division. “Our sponsorship of this trial demonstrates our dedication to partnering with physicians to answer the many questions that exist about the treatment of AF.”

AF is the most common abnormal heart rhythm and affects an estimated 2.3 million people in North America and 4.5 million Europeans. AF is responsible for 15 to 20 percent of all strokes, is a contributor to heart failure and is a leading cause of hospitalizations.

Heart Rhythm 2009 takes place May 13-16 at the Boston Exhibition and Convention Center. The meeting is the most comprehensive educational event on heart rhythm disorders, offering approximately 250 educational opportunities in multiple formats. The world’s most renowned scientists and physicians will present a wide range of heart rhythm topics including cardiac resynchronization therapy, catheter ablation, cardiac pacing and heart failure and the latest technology, including state-of-the-art pacemakers and defibrillators. http://www.HRSonline.org.

Source
St. Jude Medical