Clot-busting drug therapy, when administered to patients after a stroke, appears to work more effectively if the patient already has been on an anti-platelet medication. However, this might also increase the risk for bleeding within the brain.
These are the conclusions of an article in the May 2008 issue of the Archives of Neurology, one of the Journal of the American Medical Association/Archives journals.
The administration of tissue plasminogen activator (tPA) to dissolve blood clots produces improved outcomes in some stroke patients. However, the medication itself is associated with a 10-fold increase in risk of symptomatic brain hemorrhage. Anti-platelet medications are thought to further increase this risk because the function of these drugs impairs the work of cells that are essential in forming blood clots.
Maarten Uyttenboogaart, MD, and colleagues at the University of Groningen (Groningen, the Netherlands), examined 301 patients who were given tPA following a stroke between 2002 and 2006. Of these patients, 89 had used antiplatelet drugs before tPA. Of the patients receiving anti-platelet therapy, 12 patients (13.4%) suffered symptomatic brain hemorrhages.
In contrast, only six patients (2.8%) of those who had not received the additional therapy did.
Thus, patients who had been taking anti-platelet therapy were at a higher risk for symptomatic brain hemorrhages.
The authors point out that this was not the only outcome; there were many positive aspects of this therapy. "Despite this increased risk, prior antiplatelet therapy increased the odds of a favorable outcome" — defined as an ability to carry out daily activities independently after three months. This means that the positive effects may outweigh the negatives.
"Therefore, our study suggests that tPA treatment should not be withheld from patients receiving antiplatelet therapy."
Aspirin can remain active in the body for four to six days, and could help prevent additional blood vessel blockage after tPA therapy, which would explain the improved outcomes.
"Larger prospective studies are warranted to further investigate the influence of antiplatelet therapy on outcome after thrombolytic therapy for acute ischemic stroke," the authors conclude.
Cytokinetics sees shares rise on positive heart drug data
Cytokinetics (South San Francisco) reported interim findings from a Phase IIa study of its drug candidate for heart failure patients, CK-1827452, showing that it was well tolerated and improved heart pumping function.
The product, a cardiac myosin activator, is being studied as a potential treatment for two different types of heart failure patients. An intravenous form of the drug is being studied as a potential treatment for patients who require hospitalization due to acutely decompensated heart failure. A pill form would be for outpatients with chronic heart failure.
In the ongoing Phase IIa study, CK-1827452 demonstrated statistically significant increases in indices of cardiac ventricular function, the company said. The news sent shares of Cytokinetics up by nearly 3%, closing at $3.50.
Michael Aberman, analyst with Credit Suisse, in a research note described the data as "in-line with our expectations and represent an important milestone for CK-452 as they confirm pharmacodynamic activity in the target heart failure population." He said that CK-452 "could be the first heart failure drug to increase cardiac output without increasing oxygen consumption." He also noted the absence of serious adverse events, which were seen in the Phase I trial, suggesting that the drug "has a manageable therapeutic window."
This is the first clinical validation that the product behaves "exactly as we would have predicted" in heart failure patients, based on prior observations in animal studies and in healthy volunteers, said Robert Blum, president and CEO at Cytokinetics.
Data from the first two cohorts of the trial will be presented at the Heart Failure Congress, an annual meeting of the Heart Failure Association of the European Society of Cardiology (Sophia Antipolis, France), in Milan in June.
In the study, CK-1827452 was administered as an intravenous infusion to two cohorts of eight patients each. Each patient was given two hours of dosing during four visits, with one placebo given at one of the visits, which were spaced at least a week apart. The dosing was tied to plasma concentrations. The patients in the study were not acutely ill, but over the long-term heart failure can lead to frequent hospitalizations or even death, Blum explained.
CK-1827452 may improve on current treatments such as diuretics, beta-blockers, and ace-inhibitors, Blum said, adding that such treatments are aimed at correcting the body's maladaptive responses to heart failure, which cause the body to increase blood pressure and hold onto excess fluids.
While there are interventions available for these problems, current treatments don't improve pumping function over the long term, he said.
When compared to placebo, CK-1827452 produced statistically significant and clinically relevant increases in Doppler-derived stroke volume and fractional shortening in association with statistically significant prolongations of systolic ejection time, according to the company.
Statistically significant correlations were observed between the increases in each of these three indices of cardiac ventricular function and increases in the plasma concentration of CK-1827452, a company statement said.
Left ventricular ejection fraction, a measurement with high variability in patients with ventricular disease, also increased with accending plasma concentrations. However, this increase in left ventricular systolic function did not reach statistical significance in these initial cohorts.
Heart rate and BP remained unchanged in the first two cohorts of the Phase IIa trial. And the interim safety data suggest that the drug candidate is well tolerated, the company said.
A third cohort of the study has been initiated, with longer I.V. infusion of 24 hours, compared to two hours in the first two cohorts. Andrew Wolff, chief medical officer at Cytokinetics, said.
Additional Phase IIa studies also are planned in the first half of this year. A catheterization lab study is expected to enroll similar patients to the ongoing study and another Phase II a study will involve the largest subset of heart failure patients, those with ischemic myocardial cardiomyopathy, in which the heart does not pump well enough due to damage from coronary artery disease and prior heart attack.
CV Therapeutics adds $175 million with royalties deal for Lexiscan
Shares of CV Therapeutics (CVT; Palo Alto, California) rose 17.6% following the news that the firm received $175 million in cash from investment firm TPG-Axon Capital (New York) in exchange for rights to 50% of royalties on North American sales of Lexiscan (regadenoson) injection.
The firm could bank an additional $10 million "commercial-related" milestone, which could be triggered within the next 12 months, said Daniel Spiegelman, CFO of CVT.
Lexiscan received FDA approval in early April for use as a stress agent in radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. CVT said it expects to submit a marketing authorization application for the product to the European Medicines Agency by the end of the year.
Ranexa is indicated for the treatment of chronic angina. Because the drug prolongs the QT interval, the current labeling advises to reserve it for patients who have not achieved an adequate response with other antianginal drugs.
CVT is seeking to have the labeling changed for use of Ranexa as a first-line treatment for chronic angina.
The FDA has set a Prescription Drug User Fee Act action date of July 27 on that indication.
Lexiscan's U.S. approval will bring to CVT a $12 million milestone payment from its partner Astellas Pharma U.S. (Deerfield, Illinois), which is marketing the drug in North America. The company expects to receive that milestone this quarter, according to Spiegelman.
CVT, which has retained the rights for Lexiscan outside the U.S., Canada and Mexico, in addition to the other half of the rights in North America, already received a $7 million milestone when Astellas submitted its approval application to the FDA for Lexiscan, which targets the A2A adenosine receptor, the receptor subtype responsible for coronary vasodilation.
Astellas has covered 75% of the development costs of the drug, Spiegelman noted.
The magnitude of the TPG-Axon deal, said analyst Joseph Schwartz, of Leerink Swann LLC Research, "is much bigger than we would expect, since physicians we have queried seem relatively uninterested in a novel cardiac stress agent."
Arguments can be made that Lexiscan has some convenience, safety and tolerability benefits over Astellas' Adenoscan (adenosine injection), the standard of care drug, he said in a research note. But, Schwartz noted, physicians generally don't view the safety, convenience or tolerability issues with Adenoscan as serious. In addition, he said, that drug goes off patent soon and "should become very cheap in a few years."
Analyst David Webber, of Broadpoint Capital, said he expects CVT's stock to respond positively to the anticipated approval of Ranexa for the front-line angina indication.
Key risk factors for CVT, he said in a research note, include the chances that Ranexa sales growth could disappoint expectations, that switching from Adenoscan to Lexiscan could be less than expected, and that the safety profile of the study submitted for the new indication — the study known as MERLIN — could be interpreted by the FDA as inadequate for a label upgrade.
Stalled by FDA, ReNeuron still working for stroke trial start
LONDON — After a further no-go decision from the FDA for a first-in-human test of its neural stem cell stroke product, ReNeuron (Guildford, UK) last month said it would regroup its resources and look to other regulators for permission to carry out the landmark trial.
Having failed to meet the promised target of getting ReN001 into the clinic by the end of 2007, the company now says it is confident of doing so by the end of this year, though it risks running out of funds. In the last reported financial results at the end of September 2007, ReNeuron had 5.7 million ($11.3 million), which was sufficient to last until the third quarter of 2008.
Shares in the company fell 5 pence, to 11, pence on news that the FDA requires yet more preclinical data.
ReNeuron said it will accelerate the process of applying to other regulators based on recent favorable face-to-face meetings. The company declined to say which regulators it is talking to, but previously has said it discussed the requirements for conducting a UK trial with the Medicines and Healthcare Regulatory Agency.
To back a move into the clinic in the UK, ReNeuron recently appointed Philip Bath, professor of stroke medicine at Nottingham University, to its clinical advisory board. Bath is an expert in drug trials in stroke at both preclinical and clinical level.
The FDA first put ReN001 on hold in January 2007. Since then the company has carried out further preclinical trials, and submitted the new data in December 2007. Then, in January, it learned those data still were not good enough for the FDA, which asked for further data and additional information. John Sinden, chief scientific officer, said that the difficulty in getting FDA approval is that the agency's perception "of these sorts of therapies is moving all the time." Sinden said the FDA has given ReNeuron, "an ever-increasing number of hurdles to deal with."
It will take several months to agree on the protocols for the new studies requested by the FDA and to generate the data required on ReN001, a clonal neural stem cell line produced from fetal brain tissue. The cell line is expanded at an industrial scale using ReNeuron's c-mycER gene, which is then switched off prior to transplantation, preventing further proliferation. The product has improved functional recovery in rat models of stroke.
The company's advisers, including people who, until recently, worked for the FDA are surprised by the continuing hold. Sinden suggested that the agency's caution may be based on data or insights from applications on similar products that ReNeuron is not privy to, but he said he believes the company has put together a very good case for the safety of ReN001. "Of course you can never say never in terms of risk," he said. "It just isn't possible to prove everything [preclinically]."
ReNeuron said it intends to proceed with its IND application and has started the process of generating the further data requested.
Sinden said that the company is "working on its financial position," and added, "We believe we will be able to treat patients before the end of the year."
AHA recommends ECG testing prior to ADHD drug use
Shire (Basingstroke, UK) the world's largest producer of pharmaceutical treatments for attention deficit hyperactivity disorder (ADHD), said it was "perplexed" by a new recommendation that all children should be given a heart test before being allowed to take its drugs.
The American Heart Association (AHA; Dallas) recommended that doctors should give children an electrocardiogram (ECG) before prescribing Shire's Adderall and similar drugs such as Ritalin by Novartis (Basel, Switzerland), because the medicines have been associated with a number of deaths.
Investors indicated a fear that requiring such tests would deter some parents from putting their children on the drugs, and Shire shares dropped in after-hours trading in the U.S.
ADHD drugs accounted for $1.2 billion of the company's sales last year, 54% of its total.
Many attention deficit drugs can boost the heart rate and blood pressure, and U.S. regulators demanded health warnings be added after more than two dozen children taking them died suddenly between 1992 and 2005.
An ECG could help identify the most vulnerable children, the AHA said. "These side effects of stimulant drugs are usually insignificant but are important to monitor for children with ADHD and certain heart conditions," it said in its statement.
Doctors are not required to follow the recommendation but the AHA is widely respected and its rulings widely adopted.
Shire challenged the recommendation, saying that there is no evidence that ECGs would be useful for everybody and said it was perplexed that the AHA had made the recommendation now, when there was no new evidence on the risks of its drugs or the effects of such screening.
"The labeling for stimulant medicines already requires cardiovascular assessment," a spokesman said.And some authorities said an ECG might deter people from seeking treatment because of the added trouble and expense.
The American Academy of Child and Adolescent Psychiatry (Washington) recently updated its treatment guidelines for ADHD, and did not recommend routine EKGs. And the AHA does not recommend screening of young athletes in order to identify cardiovascular risks.