A CD&D

A U.S. physician insists that current regulatory policies should be strengthened to ensure acceptable cardiovascular safety of medicines primarily developed for non-cardiovascular applications.

Dr. Jeffrey Borer, an authority in cardiovascular medicine and surgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center (New York), recommends earlier testing for the cardiovascular effects of all drugs. He also stresses the importance of authorizing regulatory bodies to mandate continuing evaluation of drug effects, even after marketing approval.

“The importance of evaluating the cardiovascular safety of new drugs has been highlighted by recent examples of drugs — anti-arthritis drugs and others — that were withdrawn from the market when unacceptable cardiovascular risks were discovered after regulatory approval,” Borer said.

“It is clear that drugs intended for non-cardiovascular problems must be more fully scrutinized than in the past in order to allow doctors and patients to be assured that risks are well defined and that they do not outweigh the benefits provided by the drugs for the individual patient. The primary strategy to achieve this goal is increasing formal observations in both pre- and post-approval studies.”

Bore says that even though a drug may be a valid cure for one condition, its cardiac physiology/pharmacology effects should be tested in animals. Additionally, he says that drugs should get similar monitoring in the early phases of human clinical use, with the definitions of adverse cardiovascular events like heart attacks and strokes standardized for all observers before the drug is administered to any patient.

Borer says that, currently, conclusions about cardiovascular adverse events is largely subjective, rather than tied to any generally accepted definitions of conditions, resulting in limitations concerning the definition of adverse events left up to each observer individually, limiting the strength of conclusions about cardiovascular safety.

Borer contends that, overall, the regulatory rules should be beefed up to make it easier to withdraw drugs from the market of companies don’t do recommended post-market studies. He also suggests that regulatory bodies be given more teeth so that they can withdraw approval of medicines, if mandated post-marketing studies have not been performed.

A report on Borer’s recommendations was recently published in the European Heart Journal.

Two pharmas seek approval of potential rival to Plavix

Eli Lilly & Co. (Indianapolis) and Daiichi Sankyo (Tokyo) have asked U.S. regulators to approve prasugrel, an experimental clot-blocking treatment to prevent heart attacks, and a potential rival to Plavix.

Lilly and Daiichi Sankyo said that prasugrel, to be sold as Effient, prevented more heart attacks and strokes in a study than Plavix, a $6.1 billion seller in 2006 for co-marketers Bristol-Myers Squibb (New York) and Sanofi-Aventis (Bridgewater, New Jersey), more patients died from bleeding.

The mixed results of the trial, reported at a medical meeting in late November, caused analysts to back away from estimates that prasugrel could generate as much as $4 billion a year. But it has been projected for potentially reaching the high millions in sales over the next three years.

The number of deaths from Plavix and prasugrel were similar because of the increased likelihood of bleeding in the group taking the new drug. Doctors at last year’s annual meeting of the American Heart Association (Dallas), where the data were presented, disagreed about whether the FDA will find prasugrel needs more testing to identify which patients may be harmed.

Prasugrel is considered key to Lilly’s plan for replacing drugs that are heading to often-patent status. They include the antipsychotic drug Zyprexa, the company’s top seller, which will lose patent protection in 2011, as well as the anti-depression pill Cymbalta and the osteoporosis medicine Evista. The three drugs generated $6.8 billion worldwide in 2006, or 43% of Lilly’s revenue.

Daiichi Sankyo, Japan’s third-largest drug maker, will market the drug in that country and with Lilly elsewhere.

In patients who weigh less than 132 pounds, are older than 75, or who have previously had a stroke, prasugrel is likelier than Plavix to cause fatal bleeding. Plavix, which may lose its patent protection in 2011, is Bristol-Myers’s best seller. Pressure’s clinical trials were designed to show the drug was superior to Plavix to convince doctors to prescribe it, even though a generic might be cheaper, Lilly’s Ware said.

“We have always viewed our competition as being generic clopidogrel, not Plavix,’’ said Ware. “We can’t have a me-too drug.”

Lilly and Daiichi Sankyo have begun another study, called Trilogy, which will begin recruiting patients in the second quarter of 2008. This trial will examine whether prasugrel is better than Plavix in patients being treated for acute coronary syndrome, a group of common heart conditions including chest pain and heart attacks. The first patient will visit the clinic in the second quarter, Ware said.

Mylan Bertek wins FDA approval for new hypertension drug

The FDA has approved Bystolic (nebivolol), a beta blocker, for the treatment of high blood pressure. Mylan Bertek Pharmaceuticals (Research Triangle Park, North Carolina) is the sponsor of Bystolic, and Forest Laboratories (New York) owns the rights for the sales and marketing.

Douglas Throckmorton, MD., deputy director of the FDA’s Center for Drug Evaluation and Research, said that Bystolic “offers a new treatment option for people who need to control their high blood pressure.”

The safety and efficacy of Bystolic in lowering blood pressure was assessed in three randomized, double-blind, multi-center, placebo-controlled clinical trials that ran for up to three months. A fourth placebo-controlled clinical trial demonstrated additional blood pressure-lowering effects when Bystolic was given with up to two other antihypertensive medications in patients with inadequate blood pressure control. In total, more than 2,000 people received Bystolic during the trials. Its efficacy during the trials was similar to those of other FDA-approved beta blockers.

The most common side effects reported by patients taking Bystolic in clinical trials were headache, fatigue, dizziness and diarrhea.

Revised desmoteplase deal could earn Paion $102 million

Paion (Aachen, Germany) recently got its stroke drug, desmoteplase, back on track by signing a new agreement with its existing partner H. Lundbeck (Copenhagen, Denmark), under which the latter firm will take on future development and global commercialization responsibility for the compound.

Paion is receiving an upfront payment of €8 million and could receive a total of €38 million and €25 million in development-based and sales-related royalties, respectively. It would also get double-digit royalties on product sales, although at a reduced rate compared to its earlier agreement with Lundbeck. Lundbeck previously held European rights only and has now expanded its position with worldwide rights.

Desmoteplase, a genetically engineered version of a clot-busting protein isolated from the saliva of the Desmodus rotundus, a vampire bat, is being developed in order to extend the stroke treatment window from three to nine hours.

Its development was derailed during the summer, when data from a Phase III clinical trial indicated that desmoteplase performed no better than placebo, while it caused symptomatic intracranial bleeding in some patients. Shortly afterwards, its North American partner, Forest Laboratories, terminated its interest in the program and returned its rights to Paion.

However, a subsequent angiographic analysis of the data indicated that a high percentage of the patients in the trial did not have a blood clot in one of the main arteries of the brain, despite the presence of a penumbra of salvageable tissue that was previously considered to be a key indicator for the presence of visible clots in larger arteries and undetectable clots in smaller blood vessels. A subgroup analysis indicated that the drug did demonstrate efficacy in patients with confirmed clots, in agreement with earlier studies, although the signal was not sufficient to be statistically significant, given the high placebo effect seen in the Phase III trial.

Paion and Lundbeck conducted the data analysis jointly, and they also consulted with stroke experts. “That has contributed to the comfort level we have reached with Lundbeck,” said Wolfgang Söhngen, Paion CEO, during a conference call.

He declined to outline a new development timeline for the product, but said that Lundbeck may launch a new Phase III clinical trial in 2H08. “With the next study, the profile of the drug will become more clear,” he said. “From our perspective, the market potential is difficult to assess at this moment.”

For Paion, this is the second – and more serious – obstacle that desmoteplase has cleared. Last year, the steering committee on the Phase III trial put a temporary hold on recruitment, following an interim safety analysis. However, that was lifted very quickly and the trial resumed without any protocol amendment.

“A vampire never really dies,” Söhngen quipped, in reference to the drug’s origin. “Desmoteplase has always shown good potential for coming back when people think it’s dead.”

FASgen reports positive results for stroke compound, C75</P>

FASgen (Baltimore) reported recent publication of research results of one of its proprietary compounds, C75, for treatment of stroke. The company is focused on the field of fatty acid synthase inhibition (FASi), one of these areas being the treatment of metabolic disease disorders, including obesity.

Because the regulation of appetite is centered in the hypothalamus in the brain, research was undertaken to evaluate the safety of the company’s compounds in the brain. An unexpected and significant discovery resulted when the studies demonstrated not only that the compounds were non-toxic in the brain, but they also provided significant neuroprotection in the case of ischemic stroke.

The company said that in the stroke model tested, C-75 reduced AMPK levels and resulted in neuroprotection by reduced stroke damage, even when administered post-stroke.

The findings were published in the article, “Neuroprotective Effects of Adenosine Monophosphate-Activated Protein Kinase Inhibition and Gene Deletion in Stroke,” McCullough et al, Stroke 2007, (Dec. 11, 2007).

FASgen was founded in 2000 by four researchers at Johns Hopkins (Baltimore) to create new therapeutic products based on the selective inhibition of fatty acid biosynthesis. The company has licensed the product from Johns Hopkins.

Analysis finds HRT benefit for early menopausal women

An analysis of several studies concerning Hormone Replacement therapy (HRT) by the American Association of Clinical Endocrinologists (AACE; Jacksonville, Florida) indicates that young women in early menopause may not only have no increased cardiovascular risk from the therapy, but may indeed show benefit in the future. This runs counter for the general concerns about HRT therapy.

HRT has powerful effects in relieving menopausal symptoms.

AACE conducted the analysis in response to several major studies that brought to light conflicting information about the safety of HRT. Those studies include the Women’s Health Initiative (WHI), The Heart and estrogen/progestin Replacement Study (HERS), and the Postmenopausal Estrogen/Progestin Interventions study (PEPI).

The AACE analysis included a meta-analysis of 23 trials that compared results in women younger than 60, or less than 10 years since menopause. When re-evaluating to permit an analysis of cardiovascular disease based on age, the studies showed that after a three year period, there was no difference in the incidence of cardiovascular disease between the HRT group and the placebo group.

Richard Hellman, MD, president of AACE, said, “Since the WHI was published in 2002, there has been much debate over the risk/reward ratio with this treatment option. Patient safety must always be our primary objective. We can now say with good confidence that this therapy is very safe for women under 60, or who have recently experienced menopause”

Cardiovascular drug news in brief ... .

• Athersys (Cleveland) and Angiotech Pharmaceuticals (Vancouver, British Columbia), received FDA clearance to start a Phase I trial of MultiStem, an allogeneic cell product, in acute myocardial infarction. MultiStem is designed to be injected directly into and around the zone of myocardial injury from an intra-coronary approach.

The companies agreed in May 2006 to co-develop and commercialize Athersys’ non-embryonic stem cell platform technology for use in AMI and peripheral vascular disease.

Upon completion of the Phase I trial, Angiotech will assume lead responsibility for further clinical development. Angiotech also owns marketing and commercial rights.

• SkyePharma (London) and Sciele Pharma (Atlanta) reported FDA approval of all four new dosage strengths of Sular, a calcium channel blocking agent for the treatment of high blood pressure. The new Sular formulation uses SkyePharma’s patented Geomatrix technology, which provides a lower dose of the drug for each of its current doses, the companies said. The firms expect to launch the new formulation this quarter. SkyePharma said it will receive $2 million on the approval and also mid-single-digit royalties on net sales of new Sular.

• PepTcell (High Wycombe, UK) has entered into a research collaboration with Gador SA (Buenos Aires, Argentina), to develop a T-cell vaccine for Chagas disease, a neglected tropical disease with no adequate treatment or vaccination, and one of the leading causes of heart failure.

PepTcell will use its technology to identify parasitic proteins capable of inducing a T-cell immune response. When the vaccine is ready to enter Phase III, Gador will assume responsibility for its development, commercialisation in Argentina and manufacturing. PepTcell will receive undisclosed royalties based on net sales.

Chagas affects about 18 million people in Latin America, and the World Health Organization (Geneva) recently set up an initiative to increase awareness and eradicate the disease by 2010.

• CV Therapeutics (Palo Alto, California) said the FDA has approved new language for the product labeling of Ranexa (ranolazine extended-release tablets), which describes the ability of the drug to inhibit the late sodium current at therapeutic levels.

Data on Ranexa’s mechanism has suggested that during ischemic episodes excess sodium can flow into cardiac cells through sodium channels, which can trigger a subsequent overload of calcium that can lead to problems with proper contraction and relaxation of the heart, the firm said. Late sodium current inhibition has been shown to improve mechanical and electrical dysfunctions of cardiac cells under these circumstances.

• Ablynx (Ghent, Belgium) reported final, positive results from a Phase I study of its lead anti-thrombotic, ALX-0081, the first therapeutic nanobody in clinical trials.

The product targets von Willebrand Factor, and is being developed to reduce the risk of thrombosis in patients with acute coronary syndrome and thrombotic thrombocytopenic purpura. A multi-dose study will follow sometime this year. ALX-0081 has progressed from discovery to completion of Phase I in just over three years.

• Corthera (San Mateo, California), closed a $23 million Series C financing. New investor Caxton Advantage Life Sciences Fund joined existing investors Domain Associates and Kleiner, Perkins, Caufield & Byers in the financing round.

Corthera said it will use the financing to advance the clinical development of its lead drug candidate, Relaxin, for the treatment of acute heart failure.

The company also reported that it named Stan Abel president/CEO. Abel was the CFO and co-founder of Cerexa and played a key role in the company’s sale to Forest Laboratories in January 2007.