AHA: cangrelor fails to find a championship season Reply

Negative results of the CHAMPION PCI and CHAMPION PLATFORM trials have put a damper on hopes for cangrelor, the potent intravenous, reversible platelet blocker under development by the Medicines Company. But investigators say the drug might not have been used properly in the trials, and say they hope to find ways to make use of the drug’s potency and rapid on and off action.

The results of the two trials were presented today at the American Heart Association in Orlando and published simultaneously in the New England Journal of Medicine. These findings follow an announcement last spring that the Medicines Company was discontinuing the CHAMPION clinical trial program.

CHAMPION PCI was stopped early after 8,820 patients had been enrolled when an interim review panel said the trial could not meet its primary endpoint. Cangrelor was compared to a 600 mg dose of clopidogrel for 48 hours following PCI in ACS patients. “There was no statistically significant difference in the primary composite endpoint (death, heart attack and ischemic revascularization at 48 hours), which affected 7.5% of the cangrelor group vs. 7.1% for the clopidogrel group,” said Robert Harrington, the study’s principal investigator.

CHAMPION PLATFORM was stopped early after enrolling 5,362 patients to either placebo or cangrelor during PCI. Following the procedure all patients received 600 mg clopidogrel. “There was no statistically significant differences between the two arms of the trial at our 48-hour endpoint,” said the study’s PI, Deepak Bhatt.

Several observations from the trials sparked hope for the future among the investigators. When results from the two trials were combined the researchers found a reduction in acute stent thrombosis, for instance. Bhatt pointed to a reduction in total mortality from 0.7% in controls to 0.2% in the cangrelor group, but said that “it is a secondary endpoint and needs to be interpreted with some caution given that the primary endpoint was not met and the number of deaths overall was low.”

“Although the results of the two trials are disappointing in that they failed to meet the primary endpoint, there is enough suggesion in these data of potential benefit that it warrants further investigation,” said Harrington.

CardioBrief readers may be interested to learn that the headline of the Medicines Company press release (reprinted at the bottom) states that the data “shows cangrelor significantly improves patient outcomes following PCI.” The press release does not mention that the trials were terminated early and failed to achieve their primary endpoints until the first paragraph. [We apologize for reporting earlier that this information did not appear in the press release until the third paragraph.]

Here are the press releases from the AHA:

New blood thinner for angioplasty patients not superior for primary endpoint, but did reduce death and stent thrombosis

ORLANDO, Fla., Nov. 15, 2009 — A new reversible blood thinner for angioplasty patients wasn’t superior over placebo for its primary combined endpoint of heart attack, all-cause mortality and need for revascularization, but it reduced mortality and in-stent blood clots, researchers reported in a late-breaking clinical trial presentation at the American Heart Association’s Scientific Sessions 2009.

CHAMPION PLATFORM, a phase III trial, included 5,362 angioplasty-plus-stent patients randomized to receive either a placebo or the investigational drug cangrelor during procedures to reopen coronary artery blockages.  Cangrelor is a potent, fast-acting and reversible anti-clotting drug delivered intravenously.

After their procedures, all patients received 600 milligrams (mg) of the oral, nonreversible anti-clotting drug clopidogrel, which is routinely used in such procedures.

The trial, which enrolled patients beginning in 2006, ended when an interim review committee concluded that cangrelor would fail to show superiority over clopidogrel for its primary endpoint: a composite of all-cause death, heart attack and the need for coronary revascularization procedures.

“There was no statistically significant difference between the two arms of the trial at our 48-hour endpoint,” said Deepak L. Bhatt, M.D., M.P.H., chief of cardiology at the VA Boston Healthcare System.  “However, a number of secondary endpoints had very interesting and informative findings.  For instance, all-cause death as a stand-alone endpoint was reduced significantly from 0.7 percent in controls to 0.2 percent (67% reduction) in the cangrelor group.

“It is intriguing, of course, but it is a secondary endpoint and needs to be interpreted with some caution given that the primary endpoint was not met and the number of deaths overall was low.”

Furthermore, acute stent thrombosis (blood clots that form within the stent) was significantly reduced in the test group.

“That’s something that interventional cardiologists really worry about because stent thrombosis is often associated with a recurrent heart attack or death,” said Bhatt, who is also director of the integrated interventional cardiovascular program at Brigham and Women’s Hospital and the VA

Boston Healthcare System and a faculty member at Harvard Medical School in Boston, Mass. “Acute stent thrombosis was reduced from 0.6 percent in controls to 0.2 percent in the test group (69% reduction), again a significant benefit.  So there seems to be a plausible mechanism by which mortality may have been reduced since stent thrombosis was reduced.”

Researchers found no difference in endpoints between test and control groups for severe bleeding and need for blood transfusion.  However, less severe bleeding was significantly higher with the new agent, 5.4 percent vs. 3.4 percent in controls, an indication of the investigational drug’s potency, Bhatt said.  Because it’s reversible and is delivered through an intravenous line, bleeding events can be ended quickly after the drug is no longer administered.

Clopidogrel is given orally and is irreversible — once it binds to a platelet it remains for the life of that blood cell, usually 7 to 10 days.  That puts clopidogrel patients at higher risk of bleeding complications if they need emergency surgery, he said.

“At least in theory, cangrelor has all the attributes that an interventional cardiologist would want: Its onset of action is very quick and it’s very potent, but on the back end you can turn it off,” Bhatt said.

The companion CHAMPION PCI trial, which had a different patient group and slightly different hypothesis, was presented at the same session.

The Medicines Company funded the study.

Co-authors of the study are the CHAMPION executive committee members.

Disclosure: Dr. Bhatt receives grant support from the study sponsor.

###

New reversible antiplatelet drug no more effective than irreversible one in PCI

ORLANDO, Fla., Nov. 15, 2009 — A new, reversible antiplatelet drug did not demonstrate superiority over a current irreversible one in reducing the composite of death, heart attack or ischemia-related revascularization in the 48 hours after angioplasty, researchers reported in a late-breaking clinical trial presentation at the American Heart Association’s Scientific Sessions 2009.

The primary endpoint for CHAMPION PCI was not met, but study researchers say they did find some potential benefit of the new drug, cangrelor, that warrants further investigation.

“Our findings combined with those from a companion trial (CHAMPION PLATFORM) suggest that cangrelor reduces the risk of some clinically meaningful ischemic events in patients undergoing percutaneous coronary intervention (PCI),” said Robert A. Harrington, M.D., principal investigator of the study and professor of medicine at Duke University and director of the Duke Clinical Research Institute in Durham NC.  “That includes a possible reduction in Q wave infarction and stent thrombosis.”

In CHAMPION PCI — a phase III, multi-national (200 sites, 18 countries), randomized, double-blind, placebo-controlled trial— researchers tested the hypothesis that cangrelor provides superior or at least non-inferior performance compared to a 600 milligram (mg) dose of clopidogrel during the 48 hours after PCI.

Investigators planned to enroll about 9,000 patients, but the trial was stopped early (May 2009) with 8,820 patients enrolled after an interim review panel concluded it was unlikely to meet its primary endpoint.

Patients were randomly assigned to receive cangrelor or clopidogrel, the FDA-approved antiplatelet drug that binds irreversibly to platelets.

Those in the cangrelor group got 30 micrograms (mcg) of cangrelor per kilogram (kg) of body weight intravenously, followed by a 4 mcg/kg/per minute infusion for at least two hours.  At the end of the procedure, they received a 600 milligram (mg) dose of clopidogrel.

Patients in the clopidogrel group received a standard 600 mg loading dose immediately prior to their PCI.  Following the procedure all patients received a maintenance dose of 75 mg of clopidogrel and aspirin therapy (75 mg to 325 mg/day) for at least 30 days thereafter.

Patients received all other anti-clotting therapies according to care standards at their treatment site.

“There was no statistically significant difference in the primary composite endpoint (death, heart attack and ischemic revascularization at 48 hours), which affected 7.5 percent of the cangrelor group vs. 7.1 percent for the clopidogrel group,” Harrington said.  But, in formal non-inferiority 1160testing, cangrelor appeared to maintain more than 60 percent of the benefit of 600 (mg) clopidogrel over placebo.

When looked at together with data from the companion trial, researchers also found a reduction in acute stent thrombosis, which are blood clots within the metal mesh stent implanted during PCI to help hold the vessel open.  The two treatment groups were well balanced in baseline characteristics. It was noted that there was more minor bleeding associated with cangrelor.

This is the first study to use a 600-mg dose (instead of 300-mg dose) of clopidogrel as the comparison drug and to compare that dose to cangrelor.  Cangrelor is the first drug in a class of intravenous P2Y12 receptor antagonists.  It provides immediate and intense inhibition of platelet clotting, but, as opposed to clopidogrel, this effect can be reversed.

“With its fast onset and reversibility, cangrelor holds the potential to provide interventional cardiologists with a very rapidly acting platelet inhibitor during PCI. Although the results of the two trials are disappointing in that they failed to meet the primary endpoint, there is enough suggestion in these data of potential benefit that it warrants further investigation,” Harrington said.

The companion CHAMPION PLATFORM trial, which had a different patient group and slightly different hypothesis, was presented at the same session.

The Medicines Company funded the study.

Co-authors are the CHAMPION executive committee members.

Disclosures: DCRI (Dr. Harrington is the Director) received research funding from the sponsor to assist with the coordination of the trial, including the trial statistical analyses. Dr. Harrington’s conflict of interest statement is available on the Duke Clinical Research Institute website.

Here is the press release from The Medicines Company:

The Medicines Company’s Full Analysis of CHAMPION Phase III Data Shows

Cangrelor Significantly Improves Patient Outcomes Following PCI

Data from Two International Trials with nearly 14,000 Patients Presented at

American Heart Association Scientific Sessions and Published in Two Papers in the

New England Journal of Medicine

FOR U.S. AUDIENCES ONLY

Parsippany, N.J., November 15, 2009—The Medicines Company (NASDAQ: MDCO) today announced the data from 13,941 patients treated in the discontinued CHAMPION Phase III program of cangrelor.  While cangrelor did not show superiority to 600 mg clopidogrel given orally for the pre-specified primary endpoint comprising death, MI, or ischemia driven revascularization (IDR) at 48 hours, full analysis of the CHAMPION program data revealed strong evidence ofpharmacological effects, clinical effectiveness and suitable safety in patients undergoing percutaneous coronary intervention (PCI).  In fact, cangrelor significantly reduced the composite endpoint of death, Q-wave myocardial infarction (MI) and IDR.

Two separate presentations on the results of the CHAMPION PCI and CHAMPION PLATFORM trials will be given today at the American Heart Association Scientific Sessions 2009 in Orlando, Florida, by Robert A. Harrington, M.D., Professor of Medicine at Duke University Medical Center, Director of the Duke Clinical Research Institute and Deepak L. Bhatt, M.D., M.P.H., Chief of Cardiology at the VA Boston Healthcare System, Director of the Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System. The speakers are the lead authors of two papers on these results published in the New England Journal of Medicine, which became available online today.

CHAMPION program data were analyzed after the program’s discontinuation in May 2009 when 98% of targeted patients in CHAMPION PCI and 84% in CHAMPION PLATFORM had been enrolled.  At that time, the program’s independent interim analysis review committee reported to the company and the principal investigators that the CHAMPION PLATFORM trial was not expected to meet its primary endpoints.

Cangrelor was superior to clopidogrel (600 mg given orally before PCI) in inhibiting platelet aggregation measured by a range of laboratory tests (p-value <0.0001) during the first 2 hours of treatment, resulting in more rapid and greater effect than that of clopidogrel. The antiplatelet effects of cangrelor are quickly reversible, enabling smooth transition to oral clopidogrel with no evidence of attenuation of clopidogrel effect.

The risk of the composite endpoint of death, Q-wave MI or IDR was 39% lower on cangrelor than on 600 mg clopidogrel given immediately before or immediately after PCI (p-value = 0.0049). Similarly, the risk of the composite endpoint of death, Q-wave MI or stent thrombosis was 45% lower (p-value = 0.0028).

In CHAMPION PCI, cangrelor was not superior to 600 mg clopidogrel loading dose in the 37% of patients who entered the trial on clopidogrel maintenance therapy.  However, cangrelor was superior to a 600 mg clopidogrel loading dose in remaining 63% thienopyridine-naïve patients with a relative risk reduction for death/Q-MI/IDR of 43% (p-value = 0.04).  In CHAMPION PLATFORM, all patients were thienopyridine-naïve and cangrelor showed a relative risk reduction for death/Q-MI/IDR of 45% (p-value = 0.0028).

“Although these endpoints were a pre-specified component of the primary endpoint, their combinations were devised post-hoc and so the data cannot be deemed conclusive,” said Deepak L. Bhatt, M.D., M.P.H “But these findings are biologically plausible and suggest superior antiplatelet effects and clinical potential.”

“The platelet sub-study of the CHAMPION PCI trial provides evidence of rapid, potent antiplatelet effect,” said Robert A. Harrington, M.D. “This is particularly important in specific patient groups, such as those urgently requiring PCI or surgery, those who cannot receive oral medication, those who are known not to respond well to clopidogrel.”

There was no significant increase with cangrelor in usual measures of bleeding, including no increase in TIMI major or minor bleeding; no increase in GUSTO severe or moderate bleeding; and no increase in the incidence of blood product transfusions. Access site hematomas were more frequent in patients on cangrelor than on comparators. Infrequent (~1%) and reversible episodes of breathlessness were also reported more frequently among patients given cangrelor.

Cangrelor is uniquely positioned in the hospital setting where patients require rapid onset, direct and rapidly reversible platelet inhibition. This may translate into important advantages for patients undergoing PCI, patients undergoing other procedures and those with conditions associated with arterial thrombosis such as acute coronary syndromes.

“We are very excited by cangrelor’s promising pharmacological data, substantial improvement of important clinical endpoints, and suitable safety. It is important that cangrelor was superior to a 600 mg clopidogrel loading dose in thienopyridine-naïve patients.  Our market research and CHAMPION PCI data show that this is the majority of patients undergoing PCI,” stated Clive Meanwell, M.D., PhD, Chief Executive Officer of The Medicines Company. “We intend to continue our dialogue with the FDA and initiate discussions with European regulators to devise the most efficient and expeditious development path forward.  We will be able to plan additional large clinical studies as well as timelines for cangrelor reaching the market after completing discussions with the regulators. In the meantime, we will commit resources to regulatory submissions and preparation of commercial-scale manufacturing. “

The company will continue enrolment in the BRIDGE study – a trial testing cangrelor as a platelet inhibitor in patients with coronary stents who need to discontinue clopidogrel prior to planned surgery. The company also will initiate various other clinical pharmacology studies.

In summary, the pharmacological effects, clinical effectiveness and suitable safety of cangrelor make this a highly attractive drug candidate for short-term platelet inhibition in hospital patients.  The compound is a valuable asset, and the Company remains committed to its further development.

Cangrelor is an investigational intravenous antiplatelet agent exclusively licensed in December 2003 from AstraZeneca.

The Medicines Company will host a conference call tomorrow, Monday, November 16, 2009 at 8:30 a.m. Eastern Time.  The conference call will be available via phone and webcast. The dial in information is listed below:

 
Domestic Dial In:   866-700-7441           
International Dial In:   617-213-8839          
Passcode for both dial in numbers:   59976774

Replay is available from 11:30 a.m. Eastern Time following the conference call through November 23, 2009. To hear a replay of the call, dial 888-286-8010 (domestic) and 617-801-6888 (international). Passcode for both dial in numbers is 10591724.

This call is being webcast and can be accessed at The Medicines Company’s website at www.themedicinescompany.com.

About The Medicines Company

The Medicines Company (NASDAQ: MDCO) is focused on advancing the treatment of critical care patients through the delivery of innovative, cost-effective medicines to the worldwide hospital marketplace. The Company markets Angiomax® (bivalirudin) in the United States and other countries for use in patients undergoing coronary angioplasty, and Cleviprex®(clevidipine butyrate) injectable emulsion in the United States for the reduction of blood pressure when oral therapy is not feasible or not desirable. The Medicines Company’s website is www.themedicinescompany.com.

Statements contained in this press release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words “believes,” “anticipates” and “expects” and similar expressions are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company’s actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether we are able to obtain or maintain patent protection for the intellectual property relating to the Company’s products, whether the Company’s products will advance in the clinical trials process on a timely basis or at all, whether clinical trial results will warrant submission of applications for regulatory approval, whether the Company will be able to obtain regulatory approvals, whether physicians, patients and other key decision-makers will accept clinical trial results, and such other factors as are set forth in the risk factors detailed from time to time in the Company’s periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company’s Quarterly Report on Form 10-Q filed on November 9, 2009, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.

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