The Medicines Company (Parsippany, New Jersey) has received U.S. approval of its intravenous drug for high blood pressure, Cleviprex, the first new IV antihypertensive to come on the market in 10 years. Cleviprex is expected to improve on current available therapies and provide a new alternative to oral therapy, the company said. The product differs from many current IV. antihypertensive agents that are metabolized by the kidney and/or liver, according to MDCO. Cleviprex is metabolized in the blood and tissues and does not accumulate in the body.

The company said it will launch Cleviprex (clevidipine butyrate) this month for use in the critical care setting, such as hospital emergency rooms, intensive care units and the operating room.

"A Cleviprex advantage is its ability to be used in patients with liver or kidney problems and with other medications, which are cleared through these two organs," Leerink Swann analyst Joseph Swartz wrote in a research note. He judged that the product has the potential to double the company's sales. Cleviprex is likely to find use in a broader market, Schwartz said, in cardiology, neurology, the emergency room and intensive care.

John Kelley, MDCO president/COO, said in a statement that Cleviprex could "treat a broad array of patients who need rapid and precise blood pressure control."

An estimated 3.4 million U.S. patients receive an I.V. antihypertensive agent each year, according to the company's figures. This year's sales are projected to reach $5 million to $10 million and peak sales could reach $225 million in 2019, Schwartz wrote. Assuming the company receives five extra years of marketing exclusivity under the Hatch-Waxman Act, 2019 is the last full year of exclusivity for the product, Schwartz said. This was a first-cycle FDA approval of Cleviprex, based on six Phase III trials of 1,406 patients. All Phase III trials met all of their primary endpoints.

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

The company's other marketed product is the blood thinner Angiomax for patients undergoing coronary angioplasty procedures. It also has a late-stage drug in development, cangrelor, an injectable anti-platelet agent for use during coronary procedures such as angioplasty.

Cangrelor was exclusively licensed in December 2003 from AstraZeneca (London). Under the terms of that agreement, The Medicines Company will have exclusive license rights to develop, market and sell cangrelor worldwide, excluding Japan, China, Korea, Taiwan and Thailand.

Angioplasty/stenting takes another hit

Angioplasty/stenting seems to be a target taking a variety of hits over the past two years, a small group of studies indicating that this minimally invasive device strategy may be used too often and too expensive compared to other therapeutic approaches.

The latest negative critique comes from a study last month in the New England Journal of Medicine which concludes that treatment with medication over time is as effective as this minimally invasive procedure in alleviating chest pain.

For the study William Weintraub of Christiana Care Health System (New Castle, Delaware) and colleagues examined 2,287 patients with stable heart disease who received a combination of medications that possibly included aspirin, statins, nitrates, ACE inhibitors, beta-blockers and calcium channel blockers. Half of the participants also underwent angioplasties and had bare-metal stents implanted .

Researchers conducted a survey of about 70% of participants and found that 78% had chest pain when the study began. According to the survey, 53% of participants who underwent angioplasties reported no chest pain after three months of treatment, compared with 42% of those who only took medication.

The conditions of participants in both groups continued to improve after six months of treatment, and the gap decreased, the survey found. After three years of treatment, participants in both groups reported similar levels of chest pain, quality of life and treatment satisfaction, according to the survey.

Weintraub said patients' conditions improve whether they undergo angioplasties or only take medication, with the angioplasty procedure generally being considerably more expensive.

In an editorial that accompanied the study, Eric Peterson of the Duke University Clinical Research Institute (Durham, North Carolina) and John Rumsfeld of the Denver VA Medical Center and the University of Colorado-Denver Health Sciences Center wrote that the study "should be enlightening and practice-changing for doctors and patients alike," and should increase the use of treatment with medication for patients with stable heart disease. Their final assessment: "A strategy of up-front angioplasty is not warranted."

The study was funded by the Department of Veterans Affairs, the Medical Research Council of Canada (Ottawa) and several pharmaceutical companies.

Information request hits Cardiome shares

Nearly seven months after Canadian firm Cardiome Pharma (Vancouver, British Columbia) and its North American partner, Astellas Pharma US (Deerfield, Illinois), expected an approval decision from the FDA for Kynapid (vernakalant), an experimental drug used to treat atrial fibrillation (AF), the agency responded with an approval but accompanied by a request for more data. Cardiome's shares slumped more than 30% the morning following the news, with afternoon recovery of about 18%, to $9.78.

The FDA issued an approvable letter seeking updated safety data from ongoing and completed trials and more information about a subset of patients who experienced certain serious adverse events to determine an acceptable risk-benefit profile.

Cardiome and Astellas, which gained the exclusive North American rights to develop and commercialize the drug under a 2003 deal, had been left waiting for a decision from the FDA since Jan. 19, the Prescription Drug User Fee Act action date. The companies had high hopes the agency would follow the Dec. 11, 2007, recommendation by the FDA's Cardiovascular and Renal Drugs Advisory Committee to approve Kynapid as a pharmacologic therapy for the acute conversion of atrial fibrillation to normal sinus rhythm. Kynapid converts the abnormal AF heart rhythm to a normal rhythm by blocking potassium channels, which predominately affect atrial repolarization, combined with a concentration, voltage and frequency-dependent blockade of sodium channels, with no effect on calcium channels. Kynapid selectively prolongs atrial refractoriness and rate-dependently slows atrial conduction.

If Kynapid is approved, it would be the first new pharmacologic cardioversion therapy available in the U.S. in more than eight years, said William Fitzsimmons, Astellas' senior VP of R&D. Currently patients commonly receive either electrical cardioversion an electric shock delivered to the heart or intravenously ibutilide or amiodarone, Fitzsimmons explained.

While Kynapid was shown to be effective in converting short-term AF, the FDA had concerns about certain adverse effects. In Phase III tests, Kynapid caused two cases of ventricular fibrillation, one fatal. While the FDA in December said it was "very likely" that the fatality was precipitated by the study participant's aortic stenosis and heart failure, regulators said there was not sufficient data available that would lend support to that hypothesis.

The agency also expressed concern that because the level of exposure to Kynapid was limited in clinical trials, there is no assurance that other cases of ventricular fibrillation will not occur when exposure to the drug increases and patients with significant structural heart disease are exposed. In the absence of data, FDA reviewers said it can only be assumed that fatal ventricular fibrillation will be observed at a rate of at least one per 1,000 patients, with other risk factors of ventricular arrhythmia administered the drug.

The FDA noted that acute myocardial infarction and advanced heart failure, two of the main causes of AF, were excluded from the Kynapid studies. Therefore, regulators said the population studied is not representative of the proposed indication for the drug.

The agency reviewers in December advised that if the drug is approved, a post-marketing surveillance program be established to detect serious adverse events, especially cardiac and respiratory effects.

Doug Janzen, Cardiome president/chief business officer, said the approvable letter from the FDA contained no surprises "in the sense that the agency hasn't identified any new patients or new problems." Rather, he said that regulators are asking the companies whether there are any new details about the subset of patients who experienced the serious adverse events. "We think we can answer that question without having to run additional clinical work."

Anthera raises $19M for anti-inflammatories

Anthera Pharmaceuticals (San Mateo, California) last month closed a $19 million Series B expansion round to advance its mid-stage clinical programs for cardiovascular and inflammatory diseases. The company previously raised about $1.5 million in seed financing and $36 million in what Chris Lowe, company CFO, called a Series A2/B1 round. The latest raise, which Lowe said the latest raise should carry the company "well into 2009."

The funding was led by new investors Caxton Advantage Life Sciences Fund and HBM BioCapital. Existing investors VantagePoint Venture Partners, Sofinnova Ventures, Pappas Ventures and Mitsubishi International Corp. also participated.

Proceeds from the financing will support Anthera's anti-inflammatory pipeline, led by oral secretory phospholipase A2 (sPLA2) inhibitor varespladib (A-002). By inhibiting upstream steps in the inflammation cascade, varespladib works synergistically with statins to lower levels of low-density lipoprotein (LDL) cholesterol.

An estimated 80% of high cardiovascular risk patients fail to meet their cholesterol goals using statins alone; thus, a drug that can enhance the effect of statins is likely to be a blockbuster. While Lowe predicted that the days of the $12 billion blockbuster may be over, as statins like Lipitor face patent expiration, he said there are "still some good $2 billion to $3 billion opportunities."

Anthera licensed its sPLA2 inhibitor program from Eli Lilly and Co. and Shionogi & Co. in 2006. In two Phase II trials, varespladib reduced the target enzyme, sPLA2, as well as LDL cholesterol and C-reactive protein in cardiovascular disease patients on background medications, including high-dose statins.

Lowe said the company is "reviewing the global registration strategy" for varespladib and will report the design of its next trial and regulatory path forward in a few weeks. Anthera said it has received "no shortage of interest" in varespladib from prospective partners, and the company is open to either partnering or taking the drug farther on its own.

Behind varespladib, Anthera is conducting a Phase II trial with an intravenous sPLA2 inhibitor, A-001, for prevention of acute chest syndrome in patients with sickle cell disease. Preliminary data are expected around the end of the year.

Briefly ...

• Actelion (Basel, Switzerland) said Tracleer (bosentan), a dual endothelin receptor antagonist, has been approved in the European Union for the treatment of patients with mildly symptomatic pulmonary arterial hypertension. Tracleer has been approved and available in the European Union since 2002 for PAH patients with WHO FC III.

• CV Therapeutics (Palo Alto, California) reported receiving approval from the European Medicines Agency for the brand name Ranexa (ranolazine). The drug is approved for use in Europe as an add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line anti-anginal therapies. The company also cited publication of a study of ranolazine in the Journal of Cardiovascular Electrophysiology, concerning its use in patients with a hereditary form of long QT syndrome called LQTC syndrome. In the study, ranolazine significantly shortened the QAT interval by 26 milliseconds in a concentration-dependent manner. Additionally, ranolazine improved diastolic function, as measured by a 13% improvement in left ventricular relaxation time. No adverse effects of ranolazine were observed in the study patients.

• Duska Therapeutics (La Jolla, California) reported receiving comments from the FDA's Division of Cardiovascular and Renal Products on a synopsis of a proposed Phase III study of ATPace for the acute treatment of paroxysmal supraventricular tachycardia. The company said it is in the process of modifying the proposed Phase III trial, based on regulators' comments and plans to submit a revised protocol to the FDA for special protocol assessment procedure approval. Duska said it intends to initiate a single, prospective, placebo-controlled, randomized trial in patients presenting to the emergency room with PSVT to demonstrate ATPace's clinical safety and efficacy.

• Epix Pharmaceuticals (Lexington, Massachusetts) has launched a Phase IIb right-heart catheter study of PRX-08066. a serotonin Type 2B receptor antagonist, in patients with chronic obstructive pulmonary disease and moderate to severe pulmonary hypertension. The single-arm, open-label study is designed to evaluate the mean pulmonary artery blood pressure change from baseline as measured directly by right-heart catheterization and also will measure the change from baseline n the standard six-minute walk distance test after three months of treatment. Patients will be treated with 500 mg PRX-08066 on day one of the trial, followed by twice-daily dosing of 200 mg of the drug for three months.

• GTC Biotherapeutics (Framingham, Massachusetts) reported completing its submission of the final portion of the biologics license application for Atryn in the U.S. The final portion of the BLA submission includes all of the clinical safety and efficacy data generated from studies of Atryn, including the pivotal study supporting product licensure. Atryn is GTC's recombinant form of human antithrombin, a plasma protein with anticoagulant and anti-inflammatory properties. The BLA requests market okay for the use of Atryn in the prophylactic treatment of deep vein thrombosis and other thromboembolisms in patients with hereditary antithrombin deficiency who are undergoing high-risk surgical and childbirth procedures. There are no other recombinant forms of antithrombin available to treat this patient population.

• Neurobiological Technologies (Emeryville, California) said enrollment in its two Phase III studies evaluating Viprinex (ancrod) for the treatment of acute ischemic stroke has reached the level of patients necessary to conduct a planned interim analysis across the two studies. NTI is studying the safety and effectiveness of Viprinex in treating acute ischemic stroke when given within six hours of stroke onset. Results of the interim analysis are expected in January, the company said.

• OrthoLogic (Tempe, Arizona) reported that its drug candidates Chrysalin (rusalatide acetage, or TP508) showed statistically significant benefit in a preclinical study assessing cardioprotective effects in a model of acute myocardial infarction. Intravenous administration of Chrysalin following the onset of ischemia profoundly reduced the infarct size. Endpoints of the study include infarct size, coronary micro-vessel function, myocardial function and apoptotic markers.