In an online paper published June 30 by Hypertension, Frank DeLano, a researcher at University of California San Diego, and Geert Schmid-Schönbein, a professor of bioengineering, describe how they successfully reversed symptoms of high blood pressure, a pre-diabetes condition called insulin resistance and immune suppression, in a spontaneously hypertensive rat (SHR), a strain predisposed to developing high blood pressure. The team used a protease-blocking drug, doxycycline that worked to reverse the multiple metabolic complications in the rat strain. Doxycycline is considered an unlikely candidate to produce this beneficial effect since it is an antibiotic more commonly used to counter bacterial infections.
The researchers found that protein receptors on the surface of SHR cells become clipped off as the animals develop hypertension. They used a visualization technique to show that after several weeks of ingesting doxycycline in their drinking water, the SHR rats developed cells that again bristled with normal CD18 and insulin receptors. The animals' metabolic conditions simultaneously improved; blood pressure normalized and symptoms of immune suppression disappeared.
"These studies indicate the first time that hypertension and cell dysfunctions associated with the metabolic syndrome may be part of an enzymatic auto-digestion process in which proteases in our body become uncontrolled and break down proteins," Schmid-Schönbein said. "Our observations provide a conceptual framework in which we can start to understand how diverse complications in the metabolic syndrome arise."
Schmid-Schönbein said his findings will likely spark follow-up studies of this mechanism in humans.
The SHR strain is a model for essential hypertension in humans because both the rodent and many humans with hypertension also develop a variety of other metabolic complications when high blood pressure strikes.
In the circulation of SHR rodents, Schmid-Schönbein and DeLano found significant levels of proteases, which are enzymes that break down proteins. Natural enzyme inhibitors found in normal healthy rats did not lower the level of protease activity in the SHR strain to normal levels.
"We were looking for a common cause of diverse but concurrent metabolic problems and we were testing our theory that enhanced proteolytic activity in the circulation may be the root cause," said Schmid-Schönbein. "In the hypertensive rat we studied, enzymes cleave extracellular portions of several protein receptors, such as the insulin receptor, so that insulin can no longer bind and facilitate normal metabolism of glucose."
Under normal conditions, the pancreas releases insulin in the bloodstream. The molecule then binds to insulin receptors on the cell-surface membrane, which signals the cells to absorb glucose, a main source of cellular energy. However, when a cell loses the binding site for insulin on the insulin receptors, it becomes "resistant," or unresponsive to insulin and no longer absorbs glucose in healthy amounts on cue, which is the problem in type 2 diabetes. "These results point to a single mechanism that explains multiple and diverse cell dysfunctions encountered in hypertensive rats, and they also suggest that a similar mechanism may be operating in humans suffering simultaneously from hypertension, diabetes, and other metabolic conditions," said Schmid-Schönbein.
"Even if future studies only support the clear linkage of hypertension to insulin receptor cleavage in the current study of SHRs, this observation should lead to many studies of how these two problems perhaps interact," wrote Bohlen in the Hypertension editorial. "To what extent this interaction is part of the cause or consequences of mechanisms associated with hypertension will remain controversial for some time to come. However, it is tempting to speculate that treatment of hypertension may be inadvertently improving insulin sensitivity and likely many other abnormalities associated with cell surface receptors that have been unknowingly damaged by protease activation associated with elevated blood pressure."
Vytorin fails to meet endpoints
Schering-Plough (Kenilworth, New Jersey) and Merck & Co. (Whitehouse Station, New Jersey), joint venture co-marketers of anti-cholesterol drug Vytorin, in July released data from a large study showing that the drug does not lower the risk of major heart valve problems and the need for related surgical procedures.
The drug performed no better than placebo at lowering the risk of major cardiovascular events in patients suffering from aortic stenosis, blocked blood flow to part of the heart. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study included 1,873 patients with aortic stenosis.
A combination of Merck's popular cholesterol agent Zocor and a newer drug, Zetia, Vytorin has been regarded as a future growth driver for both companies, but sales have been down since release of a study in January indicating that it wasn't any more effective in treating heart disease than generic versions of Zocor, which are substantially cheaper.
Vytorin also failed to meet a secondary goal of improving aortic valve disease events, which included valve replacement surgery, hospitalization because of heart failure, and death related to heart. And the drug also failed to meet the secondary endpoint of reducing atherosclerotic disease.
Events included in the study assessment were non-fatal heart attacks, the need for bypass surgery and strokes. Researchers also said the discovered more cancer deaths in patients taking Vytorin, though the study said that data is based on a small number of people and could have occurred by chance.
With the negative reports from the studies, shares of Schering-Plough fell 14% to close at $18.39, and shares of Merck dropped 4%, closing at $36.11.
Before release of the study data, the companies cancelled release of their earnings reports, apparently hoping to head off more criticism over their handling of sensitive study data.
Data from the studies of the drug also indicated a higher cancer risk, and the companies sent a letter to physicians affirming its position that the spike in cases of cancer, and deaths from cancer, is an "anomaly." The companies maintain that the actual number of patients who died of cancer was too small to link to Vytorin.
Cortria eyes dyslipidemia drug
A marriage of interests between venture capital firm Domain Associates (Princeton, New Jersey) and MVM Life Science Partners (London) has resulted in the formation of Cortria Corp., focused on developing drug therapeutics for cardiovascular disease.
The company's name combines the Latin terms for "heart" and the concept of a three-tiered approach to treating heart disease. This will be done by monitoring low-density lipoproteins, high-density lipoproteins and triglycerides, said Daniel Grau, CEO and vice chairman of Cortria's CEO and chairman.
The company is banking on its triple strategy for addressing cardiovascular ailments and on its ability to treat dyslipidemia without the common therapeutic side effects of skin flushing. Early clinical trials that have shown promise for TRIA-662, the company's first product candidate, currently in Phase II clinical development for the treatment of dyslipidemia, an atherogenic disorder characterized by abnormal lipid levels in the bloodstream.
TRIA-662 contains 1-methylnicotinamide, a metabolite of niacin provided in the vitamin B3. Niacin was one of the first agents proven in clinical trials to extend life for patients with atherogenic cardiovascular disease, but often causes severe skin flushing, prompting many patients with dyslipidemia to discontinue niacin therapy.
"It literally makes patients feel that their faces are on fire," said Stephen Reeders, founder and managing partner of MVM.
Previous efforts to develop a "flush-free" niacin therapeutic, using extended release formulations, dose titration and fixed-dose combination technologies, have not succeeded. Thus, the discovery that a niacin metabolite, which does not induce flushing, could provide benefit to dyslipidemia sufferers.
The specific therapeutic properties of TRIA-662 were discovered and patented by scientists at the Technical University of Lodz (Lodz, Poland), and the patents were subsequently acquired by Pharmena (also Lodz), a pharmaceutical company. Currently, Cortria and Pharmena own the intellectual property covering the pharmaceutical compositions, as well as the monotherapy and combination uses of 1-methylnicotinamide. The companies have signed an exclusive cross-license agreement to this intellectual property, but Cortria is leading product development.
Grau said that TRIA-662 is currently in a substantial Phase II dose-ranging trial in about 200 patients. "The trial has enrolled exceptionally well and we expect data from the Phase II trial in early 2009," he said. The study is being conducted by the Montreal Heart Institut.
TRIA-662's success in Phase II will determine its future pathway, Grai said. "As we look forward into 2009-2010, we can envision, with positive data from the current trial, moving into several different opportunities," Grau said. He added: "A large percentage of patients diagnosed with dyslipidemia are already taking a statin. And for those patients, he said, there is a significant need for agents that can provide additional benefits with respect to triglyceride reduction and increasing high-density lipoproteins."
Positive results for Cleviprex
The Medicines Co. (Parsippany, New Jersey) reported that the results of ESCAPE-2, a pivotal Phase III efficacy trial of its investigational agent Cleviprex (clevidipine butyrate) injectable emulsion, were published in the July issue of the journal Anesthesia and Analgesia. The trial demonstrated that Cleviprex is effective and safe in the rapid treatment of acute hypertension after cardiac surgery.
ESCAPE-2 examined the efficacy/safety of Cleviprex in treating patients with acutely elevated blood pressure after cardiac surgery. A total of 110 patients with a systolic blood pressure (SBP) greater than 140 mm Hg following cardiac surgery were randomized to a 30 to 60 minute infusion of Cleviprex or placebo. The primary endpoint was the incidence of treatment failure, defined as the inability to decrease SBP by 15% or more from baseline, or discontinuation of study treatment for any reason within the 30-minute period after study drug initiation.
The study demonstrated:
• Treatment success achieved in significantly more Cleviprex-treated patients than placebo-treated patients (91.8% vs. 20.4%, P <0.0001).
• Median time to achieving target systolic blood pressure with Cleviprex was 5.3 minutes (95% confidence interval, 4 to 7 minutes).
• No clinically significant increase in heart rate from baseline observed, and adverse event rates were similar for both treatment groups.
"These additional data build upon the findings of the ESCAPE-1 trial, which indicated that Cleviprex was effective and safe in study patients with acute elevations of blood pressure prior to cardiac surgery," said lead investigator Neil Singla, MD, Department of Anesthesia, Huntington Memorial Hospital, Pasadena, California. "Together, both ESCAPE trials suggest that Cleviprex could be a promising drug for acute hypertension patients undergoing cardiac surgery."
Cleviprex is an IV anti-hypertensive for acute blood pressure management in the critical care setting, when the use of oral therapy is not feasible or desirable. Cleviprex is metabolized in the blood and does not accumulate in the body.
Okay of rivaroxaban recommended
The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the anticoagulant rivaroxaban (brand-named Xarelto), taken as one tablet, once-daily, for the prevention of venous blood clots (deep vein thrombosis [DVT] and pulmonary embolism [PE]) in patients undergoing elective hip or knee replacement surgery. Approval by the European Commission to provide market authorization for the drug in all EU member states, is expected in the next few months..
Bayer HealthCare (Leverkusen, Germany) submitted the regulatory filing in October 2007 for rivaroxaban for prevention of VTE in patients undergoing major orthopedic surgery of the lower limbs.
The recommendation for approval of rivaroxaban is based on review of the RECORD clinical trial in which rivaroxaban, an oral, direct Factor Xa inhibitor, demonstrated its significant clinical potential when compared to the current standard of care, enoxaparin, an injectable low molecular weight heparin (LMWH).
Involving nearly 10,000 patients undergoing elective hip or knee replacement surgery, the Phase III RECORD trials demonstrated superior efficacy of rivaroxaban in head-to-head comparisons with enoxaparin (RECORD 1&3) and when comparing extended-duration, rivaroxaban with short duration enoxaparin (RECORD 2). In all three trials, rivaroxaban and enoxaparin had comparable safety profiles and similar low rates of bleeding. The limitations of current treatment mean that many patients still do not receive satisfactory anticoagulant therapy to prevent potentially fatal clots.
"The prevention and treatment of thrombosis remains a challenge for patients requiring chronic therapy. The availability of agents such as rivaroxaban has the potential for a substantial impact on patient care," said Ajay Kakkar, professor of surgical sciences at the London School of Medicine and a principal investigator in the RECORD program.
Beverley Hunt, medical director for Lifeblood: The Thrombosis Charity, said, "Hospital-acquired DVT is a major patient safety issue. A treatment which improves upon our current standard of care as well as making extended thromboprophylaxis more accessible is an extremely important advance."
In November 2007, the All Party Parliamentary Thrombosis Group (APPTG) published a report following an audit of acute hospital trusts which found that only 32% of hospital trusts are taking steps to risk assess patients (for VTE) and bring their practices in line with NICE and government recommendations5 which are as follows:
The trade name of rivaroxaban is expected to be Xarelto, pending health authority approval.
In brief ...
• Amarin (Dublin, Ireland) said that as the result of recent discussions with the FDA, it will proceed with a Phase III trial of AMR101, an ultra-pure ethyl ester of eicosapentaenoic acid, in hypertriglyceridemia, a condition in which patients have high blood levels of triglycerides and associated with increased levels of heart disease. AMR101 has been tested in central nervous system disorders in several double-blind, placebo controlled studies, including Phase III trials in Huntington's disease. The firm said that over 900 patients have received AMR101, with over 100 receiving continuous treatment for a year or more.
• Symphogen (Lyngby, Denmark) and Biovitrum (Stockholm, Sweden) reported the first patient recruitment into a Phase II trial, initiated in June, to evaluate the safety and efficacy, and explore the dose range of Sym001, a recombinant, polyclonal anti-Rhesus D antibody, in idiopathic thrombocytopenic purpura (ITP) patients. ITP is an autoimmune bleeding disorder characterized by abnormally low platelet levels, making it difficult for the blood to clot normally. The study will observe the increase in platelet levels and explore the mechanism of action of Sym001 by assessing its binding to red blood cells.
• Spending on statins increased 156% between 2000 and 2005, according to a recent report by the Agency for Healthcare Research and Quality (AHRQ; Washington). AHRQ said that spending on statins jumped from about $8 billion to almost $20 billion during the five-year period. Statins include drugs such as Lipitor, Lescol, Pravachol and Zocor. AHRQ's analysis also found that the number of people who bought at least one statin increased from about 16 million to 30 million; the total number of outpatient prescriptions for statins rose from about 90 million to 174 million; average annual spending by individual statin users no matter who paid increased from $484 to $661.