CD&D National Editor and Staff Reports
A novel strategy for targeting drugs in cardiovascular therapy is being pursued by researchers at Emory University (Atlanta) and the Georgia Institute of Technology (Georgia Tech; Atlanta). They started by building on previous research demonstrating the use of experimental anti-inflammatory medications injected into the heart to reduce damage following myocardial infarction, but always accompanied by significant toxicities.
Michael Davis, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, told Cardiovascular Devices & Drugs that the primary goal of his team's research was to reduce the toxicities associated with SB239063, an experimental anti-inflammatory. Their method for doing this: a single injection of micron-sized particles, those particles embedded with anti-inflammatory drugs, the beads then absorbed and carried away by natural bodily processes.
In this proof-of-concept study, they used rats, injecting the microparticles following simulated heart attacks. The results showed that the procedure resulted in significant reduction of inflammation and scarring of the heart and boosting its ability to pump blood several weeks later.
Davis is senior author of a study using the microparticle approach, appearing in the October/November edition of Nature Materials.
"Other groups had used injections into the heart to see if they could get enough of these drugs there. They did things like direct injections twice a day, for weeks at a time."
But he said that the method came with significant systemic toxicities, making the method of delivery impractical. "There are clear issues if the whole body is exposed to the drug."
As an alternative, Davis and graduate student Jay Sy turned to microscopic particles made of a material called polyketals, developed by co-author Niren Murthy, PhD, assistant professor of biomedical engineering.
The microparticles break down over a few weeks in the body, releasing SB239063. The drug has been shown to inhibit MAP kinase, an enzyme which is important during the damaging inflammation that occurs after a heart attack. When the particles were injected nto rats' hearts, the researchers could see an inhibition of the MAP kinase enzyme lasting for a week. However, the effect on heart function was greater after 21 days. Davis says this result suggests that the main way the particles helped the heart was to prevent the scarring that sets in after the initial tissue damage of a heart attack.
He said the drug gradually leaches out of the polyketal particles, half gone after a week of just sitting around in warm water. In addition, the microparticles are broken down by white blood cells called macrophages.
In their work with rat hearts, he said the goal was to get directly to the specific cells of the heart musculature "because they're involved in the inflammatory response in the heart. The macrophages can surround and eat the particles, or fuse together if the particles are too big."
Polyesters such as PLaGA (polylactic-co-glycolic acid) are approved for use in sutures and grafts. But Davis said that when they are made into particles small enough to be broken down in the body, polyesters cause inflammation — exactly what the drugs are supposed to stop.
Davis said that the polyketal particles provide a platform for a variety of uses. "You can control the size" — basically from 10 microns to 20 microns – "and the hydrolysis rate, to alter the release rate [and change] how quickly they degrade. They can be made to have a lot of different properties."
Davis said that the next step in their heart therapy work will be to use the microparticle approach in larger animals, primarily pigs. That could take, he estimated, another two years of work.
In humans, he said that the microparticles could be injected using current catheter technologies. Though he said he couldn't predict when the approach might be used in human trials, Davis put the current development of the concept — from first idea (a 1) to clinical use in humans (a 10) — at a 5. Davis said he and Murthy also are exploring the method for delivering drugs or proteins in other organs, such as the liver, lungs and spinal cord.
The research was funded by EmTech Bio (Atlanta), a support program for affiliate companies of Emory University and Georgia Tech; the National Science Foundation; the National Institutes of Health; the Department of Homeland Security; and Johnson & Johnson (New Brunswick, New Jersey).
Insurance policies slow heart treatment
Patients who received urgently needed medication immediately after artery-opening surgery had fewer heart attacks and re-hospitalizations following their surgeries, according to a study published in the New England Journal of Medicine. Study author Cynthia Jackevicius, PharmD, associate professor for pharmacy practice and administration at Western University of Health Sciences (Pomona, California), said the study found that adopting less restrictive health insurance policies for clopidogrel (Plavix) resulted in improved cardiovascular outcomes.
"The restrictive drug policy we assessed in this study is called prior authorization, which is a commonly used strategy in American and Canadian drug plans to prevent unwarranted and excessive use of medications," Jackevicius said. "Our study provides some evidence for rethinking how medications are restricted in drug plans, suggesting that drug policies can impact patient outcomes."
The study, "Cardiovascular Outcomes after a Change in Prescription Policy for Clopidogrel," looks at the population-level effect of a change in a pharmacy benefits program in Ontario, Canada from a prior-authorization policy to a less restrictive, limited-use policy on access to clopidogrel among patients who underwent angioplasty with stenting after a heart attack.
Patients obtained their medication immediately upon hospital discharge with the less restrictive policy but waited an average of nine days to get their medication with the prior-authorization policy. The rate of clopidogrel use within 30 days after hospital discharge following a heart attack increased from 35% in the prior-authorization period to 88% in the limited-use period.
The study looked at cardiovascular outcomes in 3,438 patients under the prior-authorization policy and 2,733 patients under the limited-use policy. The percentages of re-admission for heart attacks, additional surgery and death were reduced from 15% to 11% in changing to the limited-use policy. Re-admission for heart attacks within a year decreased from 5% to 3%.
"The methods for restricting urgently needed medications may need to be reconsidered in order to prevent unnecessary delays in receiving specific medications," Jackevicius said. "Some options include online approval, prescribing according to specific criteria, use only by authorized prescribers, or approving a short-term temporary supply that could then be assessed for prolonged use."
NitroMed Sells BiDil for $26 million
NitroMed (Lexington, Massachusetts) recently agreed to divest its low-selling heart failure drug, BiDil, to JHP Pharmaceuticals (Parsippany, New Jersey) for $26.3 million, leaving NitroMed with a modest chunk of cash and a nitric oxide technology platform.
Kenneth Bate, president/CEO/interim CFO for NitroMed, called the deal "the best opportunity for the company," which underwent a drastic restructuring process in January, cutting 70 of 90 jobs and halting active promotion of BiDil, a single-pill combination of isosorbide dinitrate and hydralazine hydrocholoride approved in 2005 as a heart failure drug targeted specifically to African-American patients, an approach raising a whole range of questions, both clinical and strategic.,
Despite the fanfare surrounding its approval as a drug aimed at a patient population that tends to disproportionately affected by heart failure – the Centers for Disease Control and Prevention reported that African-Americans between the ages of 45 and 64 are 2.5 times were likely to die prematurely from heart failure than comparable aged non-blacks – BiDil failed to live up to its marketing potential. NitroMed had projected $20 million for its first full year of sales – analyst estimates were even higher, expecting as much as $44 million in 2006 revenue. But the drug pulling in a mere $12 million.
Its lack of commercial success was attributed partly to the fact that the FDA approved only a one year shelf life for the drug. But NitroMed's biggest struggle has been trying to convince doctors to prescribe costly BiDil instead of just writing prescriptions for the two separate generic components of the drug.
NitroMed reported third-quarter revenue from BiDil sales of $4 million, and Bate told investors in a conference call that prescriptions of the drug have held steady over the past year, even without promotional efforts. The company will continue marketing the drug, without promotion, through the completion of the sale to JHP, expected in early 2009.
JHP will pay NitroMed about $24.5 million in cash, plus up to another $1.8 million for closing date inventory of the drug. In exchange, JHP gets most of the assets related to BiDil, including an extended-release version of the drug in development.
As of Sept. 30, the company had about $17.8 million in cash and about 46 million shares outstanding. Besides its cash, the remaining company assets include its nitric oxide intellectual property. Bate said the firm will continue to seek strategic alternatives, though he declined to go into details.
About 26% of the company is owned by funds affiliated with HealthCare Ventures, Rho Ventures and Invus Public Equities.
Osteoporosis drug an AF risk
People who take bisphosphonates for osteoporosis may be at risk for serious atrial fibrillation (AF), according to a new study. The research, presented at CHEST 2008, the 74th annual international scientific assembly of the American College of Chest Physicians (ACCP; ), shows that people taking alendronate or zoledronic acid, two common medications to prevent or slow the occurrence of osteoporosis, were significantly more likely to experience serious AF, including hospitalization or death, compared with placebo.
AF "can be serious if it is persistent or occurs in people with pre-existing heart disease or hypertension," said Jennifer Miranda, MD, of Jackson Memorial Hospital (Miami). "If left untreated, it can lead to pulmonary edema, congestive heart failure, or the formation of a blood clot that can cause a brain embolism and stroke."
In a meta-analysis, Miranda and colleagues from the University of Miami evaluated the relationship between the use of bisphosphonates and AF. Three studies met eligibility criteria and included a total of 16,322 patients, of whom 76% to 100% were women using bisphosphonates for osteoporosis with a mean age range of 69 to 75.
Patients in the study were taking alendronate or zoledronic acid. The analysis showed that 2.5% to 3% of patients taking bisphosphonates experienced AF and 1% to 2% experienced serious AF, including hospitalization or death. Patients taking bisphosphonates were more likely to experience AF than patients receiving placebo, and up to two times more likely to experience serious AF than patients receiving placebo.
"In patients with increased risk factors for atrial fibrillation, clinicians should be more cautious when choosing treatment for osteoporosis and weigh the risks against the benefit of decreased fracture risk," said Miranda.
"Bisphosphonates are widely used to treat millions of women and men who suffer from osteoporosis," said James Mathers Jr., MD, president of the ACCP. "A potential link between bisphosphonates and atrial fibrillation warrants additional research in this area."
Telmisartan effective for Asian patients
New results from the landmark ONTARGET Trial show that, in Asian patients at high risk of cardiovascular disease (CVD), telmisartan (Micardis) 80 mg is as effective as, and better tolerated than, ramipril 10 mg in reducing the risk of cardiovascular death, heart attack, stroke and hospitalization for congestive heart failure. The preliminary results were presented at the 19th Great Wall-International Cardiology Congress (GW-ICC) in Beijing, China.
Telmisartan and ramipril were equally protective in Asian and non-Asian populations. Of note, telmisartan was significantly better tolerated than ramipril in this Asian population, with 19.9% patients stopping their treatment permanently with ramipril, compared with only 14.4% patients treated with telmisartan (p=0.0004). Even though only patients considered tolerant of both treatments were selected to enter ONTARGET, 5.9% of patients on ramipril stopped their treatment due to cough — an adverse reaction to ACE-inhibitors — compared with only 1.4% of patients treated with telmisartan.
The researchers said that analysis will be conducted in the near future to further examine these findings.
Professor Tony Dans, of the University of the Philippines College of Medicine, the ONTARGET Trial coordinator for the Philippines, said the ONTARGET data "are very important for treatment of Asian patients at risk of cardiovascular disease. Long-term efficacy and tolerability of treatment in these patients is of prime importance to ensure that they remain on their medication and are well protected. Telmisartan is shown to be a very good treatment option for these high-risk patients."
The ONTARGET Trial involved more than 25,620 patients, including 3,137 patients from 79 centers across the Asia-Pacific region. Patients were already receiving standard care such as statins, antiplatelet therapy and also betablockers and other antihypertensive treatment, ensuring controlled blood pressure from the beginning of the trial. All patients were considered to be tolerant of ACE-inhibitors.
Worldwide, 10% to 39% of patients are intolerant to widely used ACE-inhibitors, such as ramipril, an effect more pronounced in the Asia-Pacific region. Studies show that nearly half of Chinese patients are intolerant to ACE-inhibitors.
The ONTARGET Trial Program comprises two parallel studies, ONTARGET and TRANSCEND: The ONTARGET Trial results show that telmisartan is as effective as the previous gold standard, ramipril 10 mg, in protecting against CV death, heart attack, stroke and hospitalisation for congestive heart failure, is better tolerated and associated with higher treatment compliance — whereas the combination of both treatments, telmisartan and ramipril, did not provide an additional benefit.
The TRANSCEND Trial results show that telmisartan 80 mg significantly reduces the risk of CV death, heart attack and stroke (by 13%) in ACE-intolerant patients already receiving current best standard care. The composite endpoint of CV death, heart attack, stroke and hospitalization for congestive heart failure was non-significantly reduced by 8%.
Telmisartan was discovered and developed by Boehringer Ingelheim (Ingelheim, Germany). The company markets telmisartan in 84 countries under the trademarks Micardis and Micardisplus (combination with hydrochlorothiazide).
In brief ….
• VasoGenix Pharmaceuticals (Kansas City, Kansas) reported that preclinical in vivo screening of a series of synthetic analogs of calcitonin gene-related peptide (CGRP), which naturally occurs in humans, retained the properties of CGRP at equal or greater potency. The company says it will select one of these compounds to pursue for treating heart failure. CGRP is concentrated in the heart, where nerves secrete it to protect the heart and keep heart cells alive, but when there is a myocardial infarction or heart failure, an insufficient amount is present to have a meaningful effect.
VasoGenix says that CGRP appears to benefit the heart in three possible ways: increasing local blood flow; protecting heart muscle cells from damage due to lack of oxygen; and modulating the immune system, which reduces inflammation and protects the heart. These benefits minimize heart muscle damage and subsequent scar tissue formation, while promoting the healing process.
G. Lee Southard, PhD, CEO and chairman of VasoGenix, said, "We expect to file an IND [investigational new drug] application with the FDA to begin human clinical trials for heart failure treatment with our selected compound, for which we have filed a composition-of-matter patent."
• Cytokinetics (South San Francisco, California) presented interim analyses of a Phase IIa trial of cardiac myosin activator CK-1827452 in stable heart failure patients at a meeting of the Japanese Heart Failure Society in Tokyo. The analyses demonstrated statistically significant correlations between CK-1827452 plasma concentration and increases in systolic ejection time, stroke volume, fractional shortening, cardiac output, and ejection fraction. CK-1827452 plasma concentration also significantly decreases heart rate and left ventricular end-systolic volume.
• The Medicines Co. (Parsippany, New Jersey) said that one-year follow-up data from the HORIZONS-AMI trial demonstrated that Angiomax (bivalirudin) significantly reduced cardiac-related death by 43 percent, improved overall survival by 31 percent and reduced major bleeding complications by 39 percent compared to heparin plus a platelet glycoprotein IIb/IIIa inhibitor in patients undergoing angioplasty. Angiomax showed an absolute reduction of 1.7% in cardiac-related death and 1.4% in all-cause death at one year. The findings were presented at the annual Transcatheter Cardiovascular Therapeutics meeting in Washington.
The company also reported a post-hoc analysis of the ECLIPSE trial at the annual meeting of the American Society of Anesthesiologists (Park Ridge, Illinois), showing that poor blood pressure control during cardiac surgery is associated with a higher risk of 30-day death, stroke, myocardial infarction and renal dysfunction, compared to patients with tight blood pressure control. The ECLIPSE trial compared intravenous antihypertensive therapies, and found that Cleviprex (clevidipine butyrate) is safe and effective for managing blood pressure in patients undergoing cardiac surgery and provides more precise blood pressure control than three commonly used intravenous anti-hypertensives: nitroglycerin, sodium nitroprusside and nicardipine.
• Athersys (Cleveland) presented data from its ongoing Phase I trial of MultiStem for individuals following acute myocardial infarction at the annual Transvascular Cardiovascular Therapeutics conference. Data showed successful administration of MultiStem in the first patient enrolled, and that the product was delivered safely and tolerated well by the patient. MultiStem is a non-embryonic stem cell product developed jointly by Athersys and Angiotech Pharmaceuticals (Vancouver, British Columbia) and delivered via a Cricket micro-infusion catheter developed by Mercator Medsystems (San Leandro, California).
• Aastrom Biosciences (Ann Arbor, Michigan) said the 30th patient has been treated in its Phase IIb RESTORE-CLI trial, marking the first step toward interim data retrieval from the study evaluating Vascular Repair Cells (VRCs) in the treatment of critical limb ischemia. After the 30th patient has been followed for one year, the company will be able to unblind and analyze the interim data.
• Regado Biosciences (Durham, North Carolina) reported enrollment completion for its Phase IIa study of REG1 anticoagulation system in patients undergoing elective percutaneous coronary intervention. The study is designed to assess whether REG1 can replace standard heparin therapy during the performance of coronary balloon angioplasty dilatation and stenting on patients at low risk for complications associated with therapy-related bleeding or heart attack.
• Savient Pharmaceuticals (East Brunswick, New Jersey) told investors in late October that there is no causality between cardiac events observed in the Phase III Puricase gout studies, and reiterated its intention to file a biologic license agreement for Puricase by the end of the month, according to a research note by Cowen & Co. analyst Rachel McMinn. But the product probably won't get approved on the first pass, and once approved, it could face a restricted label, McMinn wrote. According to Savient, there were seven deaths in the pegliticase program, three of which were attributed to cardiac events.
• Vitae Pharmaceuticals (Fort Washington, Pennsylvania) in October reacquired all rights to its renin inhibitor program from GlaxoSmithKline (GSK; London). The companies had entered a potential $175 million partnership focused on cardiovascular disorders in 2005, but GSK's recent reprioritization did not include heart-related conditions. Vitae did not disclose its total payments received prior to dissolution of the partnership or whether payment was required to regain rights to the compounds.