Merck’s Thrombin Receptor Antagonist Suffers Major Setback

Merck’s thrombin receptor antagonist, vorapaxar, has suffered a major setback in its clinical trial program. In one trial, TRACER, the study drug is being discontinued and the trial will be closed out. The second trial, TRA-2P TIMI 50, is being curtailed but not stopped. The actions were based on recommendations from the combined Data and Safety Monitoring Board (DSMB) for the trials. In a letter to investigators from the study chairs no explanations were offered about the reasons for the changes. Vorapaxar is a selective PAR-1 (Protease Activated Receptor 1) thrombin receptor antagonist intended to fight clot formation.

In TRACER, 13,000 hospitalized ACS patients were randomized to placebo or vorapaxar in addition to standard care. Merck announced that TRACER had accumulated the predefined number of primary and major secondary endpoints, but not all patients had received the drug for the prespecified one-year followup.

In TRA-2P TIMI 50 more than 25,000 patients with MI, ischemic stroke, or peripheral vascular disease were randomized to either vorapaxar or placebo in addition to standard care for the secondary prevention of MI and stroke. Merck said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial. The study drug will be continued in patients with previous MI or peripheral disease, representing approximately three-quarters of the study population.

In the letter to investigators from the study chairmen at the Duke Clinical Research Institute and the TIMI group, no explanations for the actions were presented. TRACER study chair Bob Harrington provided a statement to CardioBrief but declined to discuss details, saying “at this point, I’d largely be offering up hypotheses, not actual data/facts and that’s probably not helpful from the Study Chair.” Here is Harrington’s statement:

It’s important to have independent, experienced DSMBs in trials like this (large global trials with new compounds). We appreciate their insight and expertise. For TRACER, we have accrued the protocol specified number of endpoint events, they recommended that we stop now and proceed with close out and analysis. You also saw the 2P recommendations. At this point, we are contacting sites and working with the global trial teams to close out the trial so that we can get the data, clean the data, do the analyses, etc. Everything I would say beyond this is speculation as we (the investigators and sponsor) remain blinded to overall efficacy and safety data.

Here is the statement issued by Brigham and Women’s Hospital and the Duke Clinical Research Institute:

Interim review alters Phase III studies of novel antithrombotic therapy

BOSTON, MA and DURHAM, NC – Following review of interim data by the independent Data Safety Monitoring Board (DSMB) for two large-scale, global Phase III trials evaluating vorapaxar, an investigational anti-clotting medication, researchers at Brigham and Women’s Hospital (BWH) and the Duke Clinical Research Institute (DCRI) announced today they are following the recommendations of the DSMB to discontinue study drug in one study among a subset of patients and discontinue study drug in the other trial in which the protocol target number of endpoint events had been reached.

Vorapaxar is a protease activated receptor-1 (PAR-1) inhibitor, which is a new class of anti-platelet heart medication that acts on a different pathway from standard therapy, including aspirin and drugs such as clopidogrel. The trials were designed to evaluate vorapaxar for the treatment and prevention of cardiac events among patients with acute coronary syndromes and those with prior heart attack, stroke, or peripheral arterial disease.

Following the recommendation of a joint DSMB, the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2ºP-TIMI 50) trial will be continued among patients in the study who had experienced a previous heart attack or peripheral arterial disease and immediately discontinued for patients in the study who had a stroke. The trial is being led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group at BWH.

“We are pleased that we have gotten a green light from the Data Safety Monitoring Board to continue the trial in more than 20,000 of the patients enrolled,” said Eugene Braunwald, MD, chairman of the TIMI Trial. “It is exciting to study a drug that may improve the care of patients who have had a heart attack or who have peripheral arterial disease. It does not appear to be appropriate in patients who have had a stroke.”

TRA 2ºP-TIMI 50 is a randomized, multi-national, double-blind, placebo-controlled study in approximately 26,500 patients with established atherosclerotic disease who received vorapaxar in addition to standard therapy. The trial has enrolled in more than 1,000 sites in approximately 30 countries. Participants are being followed for a minimum of one year.

The TRA 2ºP-TIMI 50 clinical trial is being conducted in parallel with the DCRI’s Thrombin Receptor Antagonist for Clinical Events Reduction in Acute Coronary Syndrome (TRA•CER) trial, for which the DSMB recommended that study drug be discontinued and also informed investigators that the protocol- required number of events had been acquired.

TRA•CER is a multicenter, international, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of vorapaxar in addition to standard of care in subjects with acute coronary syndrome.

TRA•CER operations are led by the DCRI in collaboration with a select group of global academic research organizations. The study includes 12,977 participants at more than 800 centers in more than 30 countries who were enrolled between December 2007 and November 2010.

The primary efficacy endpoint of the study was the first occurrence of any component of the composite of cardiovascular death, heart attack, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization. The key secondary efficacy endpoint was the first occurrence of any one of the composite of cardiovascular death, heart attack, and stroke.

“While this is an unexpected development, the requisite number of endpoints has been acquired, which provides us with enough information to definitively answer the questions posed by the TRA•CER trial,” said Robert Harrington, MD, director of the DCRI and TRA•CER study chairman. “We are focused on working with our colleagues to conduct a timely closeout of the trial and complete a full analysis of the findings.”

The TRA 2ºP-TIMI 50 and TRA•CER trials are funded by Merck & Co, which is developing vorapaxar.

About BWH

Brigham and Women’s Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is the home of the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $ 537 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses’ and Physicians’ Health Studies and the Women’s Health Initiative. For more information about BWH, please visit www.brighamandwomens.org

About DCRI

Duke Clinical Research Institute (www.dcri.org), the world’s largest academic clinical research organization, is known for conducting groundbreaking multinational clinical trials, managing major national patient registries, and performing landmark outcomes research. Though best known for pioneering research in cardiology, the DCRI research spans multiple disciplines, from pediatrics to geriatrics, primary care to subspecialty medicine, and genomics to proteomics. The DCRI also is home to the Duke Databank for Cardiovascular Disease, the largest and oldest institutional cardiovascular database in the world, which continues to inform clinical decision-making 40 years after its founding.

###

Here is the statement issued by Merck:

Merck Statement on Changes to Clinical Studies of Vorapaxar

WHITEHOUSE STATION, N.J., Jan. 13, 2011 – Merck (known as MSD outside the United States and Canada) today provided the following statement on the changes to the clinical studies for vorapaxar, one of the Company’s investigational cardiovascular medicines, following an announcement from the two academic centers leading the studies of vorapaxar.

Merck is studying vorapaxar in two major clinical endpoint trials to evaluate the investigational medicine for the prevention of cardiac events: TRACER, a study in patients with acute coronary syndrome, and TRA-2P (also known as TIMI 50), a study in patients with prior heart attack, stroke and peripheral artery disease. Both studies are event-driven trials in which patients were planned to be followed for a minimum of one year, and both had completed enrollment.

The combined Data and Safety Monitoring Board for the two studies has reviewed the available safety and efficacy data, and made recommendations for study changes to the chairpersons. The study chairpersons have agreed to implement these changes, and communicated the following information to study investigators:

  • In the TRACER study, patients will discontinue study drug and investigators are to begin now to close out the study in a timely and orderly fashion.
  • In the TRA-2P study, study drug will be continued in patients who had experienced a previous heart attack or peripheral arterial disease (approximately 75 percent of the patients enrolled in the study), and will be immediately discontinued in patients who experienced a stroke prior to entry into the study or during the course of the study.

Merck plans to update its projections for regulatory filings for vorapaxar once the Company has received the efficacy and safety data from TRACER and can determine an updated completion date for TRA-2P.

TRACER has accumulated the pre-defined number of primary and major secondary endpoints, although not all patients will continue to receive study drug through the pre-specified one-year follow up. Merck continues to expect that the efficacy and safety data from TRACER will become available later this year and will be submitted for presentation at appropriate medical meetings.

“Cardiovascular disease remains the world’s leading killer, and despite all of the advances that have been made in the field, millions of patients remain at risk for major cardiovascular events,” said Peter S. Kim, Ph.D., president, Merck Research Laboratories. “We remain committed to conducting large clinical trials such as TRACER and TRA-2P that are so critical to understanding new cardiovascular medicines and to advancing the standard of care for patients with heart disease. We thank the investigators and the patients involved in these two studies for their continued efforts to understand the potential role of vorapaxar in the treatment of cardiovascular disease.”

Additional Background
Vorapaxar is a selective PAR-1 (Protease Activated Receptor 1) Thrombin Receptor Antagonist designed to diminish thrombosis (clot formation).

TRACER is an acute care (hospital-based) study of approximately 13,000 patients with non-ST-segment-elevation acute coronary syndrome. In TRACER, vorapaxar was administered starting with a 40 mg loading dose, followed by a 2.5 mg daily dose. The study completed enrollment in June 2010.

The primary endpoint of TRACER is the first occurrence of any component of the composite of cardiovascular death, heart attack, stroke, recurrent ischemia with re-hospitalization, and urgent coronary revascularization, compared to active control. (Clinicaltrials.gov identifier:NCT00527943; A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of SCH 530348 in Addition to Standard of Care in Subjects With Acute Coronary Syndrome: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome.)

TRA-2P, or TIMI 50, is a chronic care, secondary prevention study of approximately 26,500 patients who have experienced a heart attack, an ischemic stroke, or have documented peripheral vascular disease. In TRA-2P, vorapaxar is administered at a 2.5 mg daily dose. The study completed enrollment in November 2009.

The primary endpoint of TRA-2P is the first occurrence of any component of the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization compared to placebo. (Clinicaltrials.gov identifier: NCT00526474; A Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis.)

Conference Call
Investors are invited to a live webcast of Merck’s conference call today at 10:00 a.m. EST by visiting Merck’s Web site, www.merck.com/investors/events-and-presentations/home.html. Institutional investors and analysts can participate in the call by dialing (877) 381-5782 or (706) 758-9927. Journalists are invited to listen in on the call by dialing (800) 399-7917 or (706) 758-9928. A replay of the webcast will be available starting at 1 P.M. today through 5 p.m. EST on Thursday, January 20, 2011. To listen to the replay, dial (800) 642-1687 or (706) 645-9291. The conference ID no. is 37368244.

About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Trackbacks

  1. […] the problems encountered with vorapaxar, Merck’s thrombin receptor antagaonist that suffered a large setback last week. TIMI investigators in the TRA-2P TIMI 50 trial have been informed by Eugene Braunwald that the […]

Speak Your Mind

*