CD&Ds

A week after Ortho Biotech Products (Bridgewater, New Jersey) reported in September that 42 patients had died in a German study of epoetin alfa in stroke patients, the FDA issued its own alert. In what is called an "Early Communication," the agency said that three months after the start of the study, 16% of the patients who had received Eprex, the epoetin alfa version sold in Europe by Janssen-Cilag (Neuss, Germany), a subsidiary of Johnson & Johnson (New Brunswick, New Jersey), had died, compared with 9% of those not treated with the drug.

Researchers at the Max Planck Institute for Experimental Medicine (Munich, Germany), had been investigating whether Eprex could improve the neurological function of patients who have experienced a stroke, an indication not yet approved for epoetin alfa.

Ortho Biotech, a J&J subsidiary that markets epoetin alfa in the U.S. as Procrit, released brief details about the deaths, a spokesman said, "because of the potential safety implications for patients."

Epoetin alfa – also marketed in the U.S. by Amgen (Thousand Oaks, California) as Epogen, – belongs to a class of drugs known as erythropoiesis-stimulating agents (ESAs), bioengineered forms of a protein made in the kidneys critical to red-blood cell production. ESAs are approved in the U.S. to treat anemia in patients with kidney disease and HIV and in cancer patients with chemotherapy-induced anemia.

The FDA noted that most of the patients enrolled in the German study were not anemic and were administered high dosages of Eprex. The trial was a double-blind, placebo-controlled, multicenter investigation in 522 adult patients with an MRI-confirmed ischemic stroke in the middle cerebral artery.

Patients were randomized to receive either placebo or Eprex at an intravenous dosage of 40,000 units daily for three days – a dosage considerably higher than what is recommended by the FDA for anemia. A recombinant tissue-type plasminogen activator (rtPA), or clot buster, also was used in the German study when clinically indicated.

Roughly half of all deaths in both groups occurred within the first seven days after starting Eprex, drug regulators said. Death from intracranial hemorrhage, or bleeding in the brain, occurred in about 4% of patients compared with 1% in the placebo group, the FDA noted.

The German institute's Hannelore Ehrenreich, the study's lead investigator, argued that the increased death rate in the intent-to-treat population was restricted to patients who received systemic thrombolytic therapy with the rtPA.

In an e-mail to CD&D's sister publication, BioWorld Today, Ehrenreich contended that the study's results were "promising" and that use of epoetin alfa in stroke patients may be "less dangerous and more beneficial than thrombolysis." Ehrenreich had called Ortho Biotech's alert "premature" and said that an article the German researchers planned to publish would clarify the study results.

Regulators said the finding of increased deaths in the German study "suggests the need to closely monitor patients enrolled in other ongoing trials for adverse outcomes and to evaluate whether the potential benefits for enrolled patients outweigh the risks in these trials." The agency said it is aware of other trials using epoetin alfa for potential neuroprotective effects of improving the functional outcomes of patients after stroke.

The FDA said it will work with ESA manufacturers and other study sponsors to evaluate the clinical parameters of the risks and benefits associated with the investigational uses of ESAs as potential neuroprotective agents.

The agency said it currently is analyzing additional data from the German study and anticipates results of those analyses in "the next several weeks," and will communicate its conclusions and recommendations to the public.

Regulators noted that the agency's early communication reflects the FDA's current analysis of available data concerning epoetin alfa and that its alert "does not mean that FDA has concluded there is a cause and effect relationship" between the drug and the emerging safety issue. "Nor does it mean that FDA is advising healthcare professionals to discontinue prescribing these products," the agency said.

EPO found to limit damage following MI

Two things happen following a heart attack – necrosis (normal cell death) and apoptosis (programmed cell death). Now researchers in Japan have found that a single intravenous dose of the hormone erythropoietin (EPO) immediately after myocardial infarction can drastically reduce or eliminate apoptosis and thereby limit the amount of damage to the heart, according to an article in the October issue of The Journal of Nuclear Medicine.

"The study's concept is very novel. We wanted to see if the area of cell death following acute coronary occlusion could be reduced by a single dose of EPO," said H. William. Strauss, MD, a physician in the Nuclear Medicine Service at Memorial Sloan Kettering Cancer Center (New York), professor of radiology at Weill Cornell School of Medicine (New York) and manuscript co-author.

He added, "Cells deprived of blood quickly begin to die. By administering 99mTc-annexin V, a radiotracer with a high affinity for apoptotic cells, we were able to view the effects of EPO on heart cells immediately following the restriction of blood flow that occurs during MI."

In the study, 18 Wistar rats were randomized into two groups. In both groups, arteries were blocked to induce a heart attack; 20 minutes later, they were unblocked. Immediately afterward, one group (treatment) received an injection of EPO and the other group of saline (non-treatment). Both groups were then injected with 99mTc-annexin V, and their hearts were examined using autoradiography to evaluate the distribution of the radiotracer.

In the treatment group, EPO therapy caused a 2.7-fold reduction of tracer accumulation, indicating a reduction in apoptosis and, therefore, less damage to heart tissue. The reduction in damage to the heart was also demonstrated by measurement of regional cardiac function, which was significantly better in the EPO-treated group. These findings suggest that EPO may be useful to prevent long-term heart damage and dysfunction after a heart attack.

"Although other drugs to inhibit apoptosis have been studied, none appears nearly as effective as a single dose of EPO," Strauss said.

EPO is a naturally occurring hormone that promotes the formation of red blood cells in the bone marrow. It was first produced artificially to aid in the treatment of anemia. More recently, scientists discovered its cardio-protective capability in minimizing apoptosis.

Apoptosis is referred to as "cell suicide" because the biochemically programmed mechanism triggers damaged cells to self-destruct, albeit in an orderly way. Researchers have found that cells can die by several pathways, only one of which is apoptosis. Because cell death is central to normal physiology and numerous disease states, research into apoptosis is ongoing in a variety of medical areas, including oncology and cardiology.

"In cardiovascular medicine, imaging of apoptosis could be highly useful in managing myocardial infarction, atherosclerotic plaques and cardiac allograft rejection. Because molecular probes such as 99mTc-annexin V are capable of imaging apoptosis in living patients, they are vital to this research," said Robert Atcher, PhD, president of SNM, an international scientific and medical association focused on molecular imaging and therapy.

"More translational research is needed to evaluate cell death pathways and their significance for imaging in the diagnosis or monitoring of disease. SNM is currently working with molecular imaging practitioners, government agencies and pharmaceutical manufacturers to streamline the process to progress promising molecular imaging agents from the laboratory into the clinical setting," Atcher said.

Pfizer moves out of cardio drug R&D

A memo leaked to the Wall Street Journal and posted online by Forbes.com in late September said that Pfizer (New York) is moving away from cardiovascular disease, and a group of other indications. The memo contradicted the company's "official" pipeline update, which listed more than 10 of the 88 programs in Phase I or Phase II trials were for indications which will be discontinued.

Pfizer's spokesperson declined to comment on business development activities.

The 10 indications supposedly getting the ax are anemia, atherosclerosis/hyperlipidemia, bone health, gastrointestinal disorders, heart failure, liver fibrosis, muscle conditions, obesity, disease-modifying approaches to osteoarthritis, and peripheral arterial disease.

The memo stated that, after months of review, Pfizer has decided to focus its R&D on six "higher priority" areas: Alzheimer's, diabetes, inflammation/immunology, oncology, pain and schizophrenia. It went on to say that varying levels of investment will continue in seven areas: asthma, chronic obstructive pulmonary disorder, genitourinary conditions, infectious diseases, smoking cessation, thrombosis and transplant. Ophthalmology is "under discussion," according to the memo.

The move away from cardiovascular-related conditions comes as Pfizer braces for the looming patent expiration of its blockbuster cholesterol-lowering drug Lipitor (atorvastatin). Hopes for potential backup drug torcetrapib – which Pfizer acquired through its $1.3 billion buyout of Esperion Therapeutics (Ann Arbor, Michigan) – fizzled when a Phase III trial turned up higher death rates.

Additionally, the memo indicated that discontinued programs may be available for out-licensing. When questioned, Pfizer's spokesperson referred to the Wall Street Journal article in which Martin Mackay, Pfizer's president of global R&D, said the company still sees value in its halted programs and will seek partners for some of the compounds.

ECLIPSE data: Positive results for cleviprex

Data from the ECLIPSE study, the largest safety program to date comparing intravenous anti-hypertensive therapies, was published in the October issue of Anesthesia and Analgesia. The results show that Cleviprex (clevidipine butyrate), an injectable emulsion from The Medicines Company (Parsippany, New Jersey), is safe and effective for managing blood pressure in patients undergoing cardiac surgery and provides more precise blood pressure control than three commonly used IV anti-hypertensives.

The ECLIPSE program enrolled 1,964 cardiac surgery patients in one of three randomized, open-label trials comparing Cleviprex to either nitroglycerin or sodium nitroprusside perioperatively, or nicardipine postoperatively. Regarding the primary safety outcome of death, myocardial infarction, stroke, or renal dysfunction at 30 days, there was equivalence among all drugs evaluated, with the suggestion that Cleviprex was superior to sodium nitroprusside in mortality (5/286, or 1.7%, vs. 13/274, or 4.7%; P=0.04).

In addition, the precision of BP control was also calculated for each patient – how much and for how long systolic BP went above or below predefined, acceptable perioperative BP ranges. Cleviprex was more effective than both nitroglycerin (P =0.0006) and sodium nitroprusside (P =0.003) in maintaining BP within a pre-specified acceptable range. Cleviprex was equivalent to nicardipine in maintaining BP within the initial broad range; however, when the BP range was narrowed, Cleviprex also was significantly better than nicardipine in reducing excursions outside the more narrow range.

John Kelley, president and COO of The Medicines Company, said, "With the recent nationwide launch of Cleviprex, hospitals now have access to therapy that should advance the management of blood pressure in surgical and critical-care settings."

Additional data from the pivotal ECLIPSE program were presented at the American Society of Anesthesiologists (ASA) meeting in Orlando, Oct. 18-22.

Cleviprex is an IV dihydropyridine calcium channel blocker. The first-cycle U.S. approval of Cleviprex was based on six Phase III trials, including the three ECLIPSE studies, and involved 1,406 patients medical and surgical patients treated with Cleviprex. All Phase III trials met all of their primary endpoints.

Cleviprex may produce systemic hypotension and reflex tachycardia. The most common adverse reactions (>2%) seen with Cleviprex are headache, nausea and vomiting.

In brief

• Aeolus Pharmaceuticals (Laguna Niguel, California) reported receiving a $175,000 milestone payment triggered by the FDA's acceptance of the new drug application for bucindolol, an investigational and pharmacologically unique beta-blocker and mild vasodilator developed for the treatment of chronic heart failure. If approved by the FDA, bucindolol could become the first genetically targeted cardiovascular therapy. CPEC LLC of Delaware, a limited liability company in which Aeollus holds a 35% stake, and Indevus Pharmaceuticals (Lexington, Massachusetts) out-licensed all rights to bucindolol to ARCA Biopharma (Broomfield, Colorado). The cash payment received by Aeolus is based on the firm's ownership interest in CPOEC.

Aeolus said that although the agreement calls for future milestone payments and royalties to it and CPEC, there is no guarantee the firms will receive such funds.

• ThromboGenics (Leuven, Belgium) said results from its multi-center, randomized, double-blinded, placebo-controlled, ascending-dose Phase II trial evaluating the safety and preliminary efficacy of the intravenous administration of microplasmin in acute ischemic stroke was generally well tolerated with no evidence of increased bleeding risk. In addition, there were no systemic bleeding events reported and no evidence of increased rate of bleeding in general compared with placebo. About 25% of patients treated with microplasmin had reperfusion, or restoration of blood flow, within eight hours of being treated compared with 10% of placebo-treated patients. Of the patients who had more severe vascular blockages, 33% treated with microplasmin achieved reperfusion compared with 14% of in the placebo group. However, due to the small number of patients in the study, neither of these end points was statistically significant. But microplasmin-treated patients had a statistically significant improvement in the level of damage to the blood brain barrier compared with those in the placebo group.

• Ikaria Holdings (Clinton, New Jersey) said pre-clinical studies showed that its hydrogen sulfide drug candidates, IK-1001, reduced infarct size and protected against myuocardial apoptosis in response to an ischemia-reperfusion injury in two studies involving a porcine model. Results of a porcine study, published in Shock, demonstrated that the compound reduced various markers of injury and provided statistically significant hemodynamic stabilization. The company expects to start a phase Iia trial in cardiopulmonary bypass surgery later this year.

• Cardiome Pharma (Vancouver, British Columbia) said that partner Astellas Pharma US (Deerfield, Illinois) said it scheduled a Nov. 14 end-of-review meeting with the FDA to discuss the new drug application for Kynapid (vernakalant hydrochloride) injection for rapid conversion of atrial fibrillation to sunus rhythm. The product received an approvable letter in august, with the agency seeking updated safety data from ongoing and completed trials, as well as further information about a subset of patients who experienced certain serious adverse events. The upcoming meeting is expected to outline the steps that need to be taken before the NDA can receive final marketing approval. Cardiome also reported that Astrellas withdrew its new drug submission for Kynapid with Canadian regulators and plans to revisit its Canadian regulatory strategy following resolution of the FDA process.

• Actelion Pharmaceuticals Canada (Laval, Quebec) said that data presented at the recent annual meeting of the European Society of Cardiology (Sophia Antipolis, France), and also published in The Lancet, showed that even in mildly symptomatic pulmonary arterial hypertension (PAH) patients (WHO functional class II – WHO FCII), the disease progresses very rapidly such that patientcs can worsen to the most severe WHO functional class III and iV in a short period of time. The findings of the reancomized, placebo-controlled EARLY (Endotheliln Antagonist tRial in mildly symptomatic PAH patients) trial indicated that treatment with bosentan may be beneficial for WHO FC II PAH patients. Bosentan (Tracleer) prevented clinical deterioration by significantly delaying time to clinical worsenging and reduced the number of patients worsenting to WHO FC III/IV.

• GTC Biotherapeutics (Framingham, Massachusetts) and Ovation Pharmaceuticals (Deerfield, Illinois) said the FDA has accepted the biologics license application for ATryn, a recombinant form of human antithrombin, as a prophylactic treatment of deep ven thrombosis and other thromboembolisms in patienets with hereditary antithrombin deficiency who are undergoinig high-risk surgical and childbirth procedures. There currently are no other recombinant forms of antithrombin available to treat that patient population. Ovation acquired the exclusive U.S. rights to ATryn from GTC under a $257 million deal in June. The FDA's acceptance of the BLA triggered a $2 million payment from Ovation to GTC. The firms are anticipating that the FDA's Blood Products Advisory Committee will review the BLA for ATryn, which received orphan drug status in January.

• Anthera Pharmaceuticals (San Mateo, California) reached an agreement with the FDA on a special protocol assessment for a Phase III trial of varespladib in acute coronary syndrome. The single, pivotal trial would combine varespladib with Lipitor for first-line treatment within 96 hours of an ACS event. Antehera said the European Medicines Agency provided advice for a similar program that includes stable coronary disease treatment. A phase iIb trial is under way in ACS.

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