Pfizer Announces Phase 3 Results of Investigational Compound Bosutinib

Pfizer Inc. (NYSE: PFE) announced that a significantly higher proportion of patients with newly diagnosed chronic myeloid leukemia who were treated with bosutinib (39 percent) experienced a major molecular response (MMR), a secondary endpoint, compared with patients treated with imatinib (26 percent) in the intent-to-treat (ITT) population (p=0.002). However, the study did not meet its primary endpoint of superior complete cytogenetic response (CCyR) rate at one year versus imatinib (70 percent vs. 68 percent, respectively, [p=0.601]), in the ITT population. These results are from a Phase 3 study of the investigational compound bosutinib as a first-line treatment in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML), called the Bosutinib Efficacy and safety in chronic myeloid LeukemiA [BELA] study. These data were presented at an oral presentation at the 52nd Annual Meeting of the American Society of Hematology (ASH) (Abstract #208).(1)

Preliminary data show that fewer patients who took bosutinib progressed to an advanced phase of the disease (n=4, 1.6 percent) compared to patients treated with imatinib (n= 10, 4.0 percent), and there were fewer deaths in the bosutinib arm (n=4, 1.2 percent) than in the imatinib arm (n= 10, 3.2 percent). Patients responding to bosutinib achieved CCyR faster than those responding to imatinib (13 weeks vs. 25 weeks, p<0.001).(1)>

A pre-specified exploratory analysis also showed that bosutinib produced a higher rate of CCyR at one year compared to imatinib when CCyR was assessed only in the evaluable patient population, 78 percent with bosutinib (n=219) compared to 69 percent with imatinib (n=241). The evaluable population was different from the ITT population in that it included only those patients who received follow-up assessments for efficacy.(1)

The most frequently reported all-grade drug-related adverse events with bosutinib were diarrhea (66 percent), nausea (27 percent), vomiting (25 percent), and rash (18 percent). The most frequent grade 3/4 adverse events with bosutinib included diarrhea (8 percent) and rash (2 percent), although no patients on the bosutinib arm discontinued therapy due to diarrhea. Gastrointestinal events associated with bosutinib had an early onset and usually subsided within the first four weeks of treatment. Most frequent grade 3/4 laboratory abnormalities with bosutinib included elevated ALT (21 percent), elevated AST (10 percent), and thrombocytopenia (7 percent).(1)

More patients on bosutinib experienced serious adverse events (25.4 percent vs. 13.5 percent) and adverse events leading to discontinuation (19.4 percent vs. 5.6 percent) than on imatinib. Adverse events leading to discontinuation were most frequently due to liver enzyme elevations in the bosutinib arm and neutropenia in the imatinib arm. There were no deaths in the study due to treatment-related adverse events. The majority of patients on both treatment arms continued on study treatment after a median follow-up of 14 months.(1)

"We are encouraged by these data, as they demonstrate early and meaningful response to bosutinib in patients with newly diagnosed CML. Given the length of time these patients are treated for CML, we need more therapeutic options to choose from since each patient is different and has different needs," said Dr. Carlo Gambacorti-Passerini, professor of internal medicine and director, clinical research unit, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy, and a lead investigator of the BELA study. "Based on my experience with bosutinib, I feel it would be an important option for patients with CML."

BELA Study Design and Other Key Studies at ASH
The BELA study is a global, open label, multicenter trial of 502 adult patients randomized to receive either bosutinib (n=250) or imatinib (n=252). The primary objective of the study was to compare the CCyR rate at one year between the bosutinib and imatinib arms in the ITT population. MMR rate at one year was a key secondary endpoint.(1) Although closed to enrollment, the study remains ongoing, and patients will continue to be followed for safety and efficacy outcomes.

Bosutinib is also being studied as a single agent in patients with previously treated chronic phase CML in an ongoing clinical trial with over 500 patients, known as Study 200. Interim results from a patient cohort of this study that have failed prior imatinib therapy and were resistant or intolerant to dasatinib or resistant to nilotinib are also being presented at the ASH annual meeting during an oral data presentation (Abstract #892, December 7).(2)

"Based on the totality of evidence from the bosutinib clinical development program, we are actively engaged in discussions with regulatory authorities which we hope will enable Pfizer to offer a new treatment option for patients with CML," said Dr. Mace Rothenberg, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit.

About Bosutinib
Bosutinib is an investigational oral dual Src and Abl kinase inhibitor.(1) It is believed that by dual inhibition of the Src and Abl tyrosine kinases, bosutinib may inhibit signaling in CML cells that allows the cells to grow, survive and reproduce.(3)

About Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML), one of the four main types of leukemia,(4) accounts for 15 percent of all leukemias worldwide.(5) A hallmark of CML is an abnormal chromosome known as the Philadelphia Chromosome, a DNA mutation that initiates a series of events leading to the development of Bcr-Abl, a tyrosine kinase that causes CML cells to grow and reproduce rapidly.(6)

Response to treatment in CML can be assessed via cytogenetic or molecular markers. A complete cytogenetic response (CCyR) indicates no cells with the Philadelphia chromosome can be found in the blood or bone marrow. A major molecular response (MMR) as measured by a polymerase chain reaction (PCR) test, means that the amount of Bcr-Abl in the blood is very low. A PCR test checks for the Bcr-Abl oncogene in leukemia cells in a blood or bone marrow sample and is sensitive enough to detect this oncogene even when doctors cannot identify the Philadelphia chromosome in bone marrow cells with cytogenetic testing.(6)

Pfizer's Commitment to Hematology
Pfizer Oncology is committed to developing therapies to treat a variety of hematologic malignancies in both adult and pediatric patient populations. Collectively, hematologic cancers represent the fifth most commonly occurring cancers and the second leading cause of cancer death. While there have been significant advancements in the treatment of hematologic cancers, there continues to be a need for new therapeutic approaches, both for newly diagnosed patients and relapsed patients. In order to deliver new options that target specific hematologic abnormalities and mutations, it is important to understand the molecular subtypes and genetic variations associated with hematologic cancers. Pfizer Oncology has biologics and small molecules in clinical development across a number of hematologic malignancies.

About Pfizer Oncology
Pfizer Oncology is committed to the discovery, investigation and development of innovative treatment options to improve the outlook for cancer patients worldwide. Our strong pipeline, one of the most robust in the industry, is studied with precise focus on identifying and translating the best scientific breakthroughs into clinical application for patients across a wide range of cancers. Pfizer Oncology has biologics and small molecules in clinical development and more than 100 clinical trials underway. By working collaboratively with academic institutions, individual researchers, cooperative research groups, governments, and licensing partners, Pfizer Oncology strives to cure or control cancer with breakthrough medicines, to deliver the right drug for each patient at the right time. For more information please visit www.Pfizer.com.

Prolia(TM) (denosumab) Receives Best New Drug Honor at Scrip Awards

Amgen (Nasdaq: AMGN) is pleased to announce that it has won the Best New Drug awardfor Prolia(TM) (denosumab), a novel treatment approved in the United States (U.S.) for women with postmenopausal osteoporosis at high risk for fracture, at the2010 Scrip Awards ceremony Nov. 4 in London. Named one of TIME's Top 10 Medical Breakthroughs of 2009, Prolia is the first treatment specifically designed to target osteoclasts, the cells that break down bone.

In addition to its novel mechanism of action, the Scrip judges highlighted Prolia's efficacy in reducing fractures and dosing regimen. Prolia, the first and only RANK Ligand inhibitor approved in the U.S. and the European Union (EU), is an every six month subcutaneous injection.

"We are honored to be recognized again by our industry peers with the Best New Drug award," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "Only last year we were recognized by Scrip for our robust pipeline, which at the time included Prolia. This medicine is the result of more than a decade of work, beginning with Amgen's discovery of a pathway that regulates bone metabolism and culminating in this important new treatment option for patients with bone disease."

Osteoporosis is a serious, chronic disease that affects 30 percent of postmenopausal women in the EU.(1) In the U.S., one in two women over the age of 50 with postmenopausal osteoporosis will experience a fracture in her remaining lifetime.(2) Postmenopausal women with osteoporosis who have experienced a fracture are at increased risk for another fracture.(2,4,5)

The annual Scrip Awards are independently judged by a panel of senior industry experts and are given to biotechnology and pharmaceutical companies for their contribution to the improvement of healthcare. For more information, visit the Scrip website http://www.scripintelligence.com/awards/

About Prolia (denosumab)
Prolia is approved for use in the U.S., the EU, Canada, Australia and Switzerland. In the U.S., Prolia is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, non-vertebral and hip fractures. The U.S. prescribing information indicates Prolia should be administered by a healthcare professional.

The pivotal three-year Phase 3 Fracture REduction Evaluation of Denosumab in Osteoporosis every six Months (FREEDOM) study in 7,808 women with postmenopausal osteoporosis demonstrated that Prolia, administered as a 60mg subcutaneous injection every six months, compared with placebo at three years resulted in:(6)

* A 68 percent reduction in vertebral fractures (4.8 percent absolute risk reduction). The incidence of new spine fractures was 2.3 percent with Prolia vs. 7.2 percent with placebo; A 40 percent reduction in hip fractures (0.3 percent absolute risk reduction). The incidence of hip fractures was 0.7 percent with Prolia vs. 1.2 percent with placebo;
* A 20 percent reduction in non-vertebral fractures (1.5 percent absolute risk reduction). The incidence of non-spine fractures was 6.5 percent with Prolia vs. 8 percent with placebo;
* Significant bone density increases at all key sites measured (8.8 percent at the lumbar spine, 6.4 percent at the total hip, and 5.2 percent at the femoral neck).

In the EU, Prolia is approved for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. Prolia is also the first and only product approved in the EU for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.

Prolia is administered as a single subcutaneous injection of 60mg once every six months. For further information on Prolia, please visit: www.prolia.com

About Denosumab Collaborations
In July 2009, Amgen and GlaxoSmithKline (GSK) announced a collaboration agreement to jointly commercialize Prolia for postmenopausal osteoporosis in Europe, Australia, New Zealand and Mexico once the product is approved in these countries. Amgen will commercialize Prolia's postmenopausal osteoporosis and potential oncology indications in the U.S. and Canada and for all oncology indications in Europe and in other specified markets.

In addition, GlaxoSmithKline will register and commercialize denosumab for all indications in countries where Amgen does not currently have a commercial presence, including China, Brazil, India and South Korea but excluding Japan. The structure of the collaboration allows Amgen the option of an expanded role in commercialization in both Europe and certain emerging markets in the future.

Amgen and Daiichi-Sankyo Company Limited have a collaboration and license agreement for the development and commercialization of denosumab in Japan.

About Amgen
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com

Original Post:

New technique to speed up drug development

Scientists working at the European Molecular Biology Laboratory (EMBL) in Grenoble, France have developed a new technique that enables them to introduce up to 15 fluorescent markers to a mammalian cell in one go. They say their findings could help speed up drug development and screening. The study was funded in part by the P-CUBE (Protein production platforms) project, which has clinched EUR 6.6 million through the Research Infrastructures budget line of the EU's Seventh Framework Programme (FP7).

EMBL's Imre Berger previously developed a technique that allowed scientists to create the equivalent of a make-up brush that is applied only once and highlights different features simultaneously. So cells could be given fluorescent labels to mark various cellular components in different colours, for example blue for the nucleus, yellow for the tubulin (a component of the cell's scaffolding), red for the mitochondria, cyan for the membranes of vesicles called endosomes, and purple for the other membrane structures. This technology was created by Dr Berger as part of a method called MultiBac and used for expressing protein complexes in insect cells.

In this latest study, published in the journal Nature Communications, Dr Berger and Philipp Berger from the Paul Scherrer Institut (PSI) in Villigen, Switzerland joined forces to take this technology a step further, adopting the concept to mammalian cells like our own for the first time. This essentially involved rapidly engineering a single vector to deliver a theoretically unlimited number of foreign genes, to a cell.

To date, the scientists have successfully delivered up to 15 genes in this way. The protein encoded by each of those genes can carry a fluorescent label, so this makes multiple labelling much more efficient than previous methods. The new labelling technique for mammalian cells, called MultiLabel, could help make drug development and screening considerably faster, since it allows scientists to precisely label many cellular components involved in a given disease process and follow them all at the same time.

"The introduction of heterologous genetic information, particularly of multiple genes, into mammalian cells is a key technology in contemporary experimental biological research," the researchers said.

"The co-expression of fluorescently tagged sensors is required to simultaneously analyse multiple parameters in living cells and the co-expression of several proteins is necessary to manipulate cell fate in stem cell biology. Current technologies for multigene expression in mammalian cells are inefficient, inflexible and time-consuming."

The team explained that MultiLabel is "a novel and highly efficient modular plasmid-based eukaryotic expression system".

The P-CUBE project aims to provide greater, free access for European users to the most advanced techniques in cloning, expression, protein characterisation and crystallisation. To this end, the British and Swiss-based scientists involved in the project regularly share expertise to improve technologies and standardise procedures, with the ultimate aim of disseminating this expertise throughout Europe.

For more information, please visit:

* P-CUBE, http://www.p-cube.eu
* European Molecular Biology Laboratory (EMBL), http://embl.fr
* Nature Communications, http://www.nature.com/ncomms/index.html

What is a Serious Adverse Event?

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious and should be reported when the patient outcome is:

Death

Report if the patient's death is suspected as being a direct outcome of the adverse event.

Life-Threatening

Report if the patient was at substantial risk of dying at the time of the adverse event or it is suspected that the use or continued use of the product would result in the patient's death.

Examples: Pacemaker failure; gastrointestinal hemorrhage; bone marrow suppression; infusion pump failure which permits uncontrolled free flow resulting in excessive drug dosing.

Hospitalization (initial or prolonged)

Report if admission to the hospital or prolongation of a hospital stay results because of the adverse event.

Examples: Anaphylaxis; pseudomembranous colitis; or bleeding causing or prolonging hospitalization.

Disability

Report if the adverse event resulted in a significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.

Examples: Cerebrovascular accident due to drug-induced hypercoagulability; toxicity; peripheral neuropathy.

Congenital Anomaly

Report if there are suspicions that exposure to a medical product prior to conception or during pregnancy resulted in an adverse outcome in the child.

Examples: Vaginal cancer in female offspring from diethylstilbestrol during pregnancy; malformation in the offspring caused by thalidomide.

Requires Intervention to Prevent Permanent Impairment or Damage

Report if you suspect that the use of a medical product may result in a condition which required medical or surgical intervention to preclude permanent impairment or damage to a patient.

Examples: Acetaminophen overdose-induced hepatotoxicity requiring treatment with acetylcysteine to prevent permanent damage; burns from radiation equipment requiring drug therapy; breakage of a screw requiring replacement of hardware to prevent malunion of a fractured long bone.

Adverse Event Reporting System (AERS)

The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The FDA uses AERS to monitor for new adverse events and medication errors that might occur with these marketed products.

Reporting of adverse events from the point of care is voluntary in the United States. FDA receives some adverse event and medication error reports directly from health care professionals (such as physicians, pharmacists, nurses and others) and consumers (such as patients, family members, lawyers and others). Healthcare professionals and consumers may also report these events to the products’ manufacturers. If a manufacturer receives an adverse event report, it is required to send the report to FDA as specified by regulations. The MedWatch site provides information about mandatory reporting.

The structure of AERS is in compliance with the international safety reporting guidance (ICH E2B ) issued by the International Conference on Harmonisation. Adverse events in AERS are coded to terms in the Medical Dictionary for Regulatory Activities terminology (MedDRA).

AERS is a useful tool for FDA, which uses it for activities such as looking for new safety concerns that might be related to a marketed product, evaluating a manufacturer's compliance to reporting regulations and responding to outside requests for information. The reports in AERS are evaluated by clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to monitor the safety of products after they are approved by FDA. If a potential safety concern is identified in AERS, further evaluation might include epidemiological studies. Based on an evaluation of the potential safety concern, FDA may take regulatory action(s) to improve product safety and protect the public health, such as updating a product’s labeling information, restricting the use of the drug, communicating new safety information to the public, or, in rare cases, removing a product from the market.

AERS data do have limitations. First, there is no certainty that the reported event was actually due to the product. FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough detail to properly evaluate an event. Further, FDA does not receive all adverse event reports that occur with a product. Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event. Therefore, AERS cannot be used to calculate the incidence of an adverse event in the U.S. population.

• AERS Data
• AERS Data Files
• AERS Statistics

How to Report Adverse Events

• MedWatch: The FDA Safety Information and Adverse Event Reporting Program
• Voluntary Reporting to FDA

1. Reporting by Consumers
2. Reporting by Health Professionals

• Mandatory Reporting by Drug/Biologics Manufacturers, Distributors, and Packers

FDA to Communicate Safety Monitoring Activities to Consumers and Health Care Professionals

The U.S. Food and Drug Administration unveiled a new source of information for patients and health care professionals on the safety of recently approved drugs and biologics.
Summaries of FDA safety analyses on recently approved products will now be periodically prepared and posted on FDA's website along with a brief discussion of the steps FDA is taking to address any identified safety issues.

Some side effects may not become apparent until after a medicine has been approved and becomes available to a larger, more diverse population than the patients who participated in clinical trials that supported approval. The new summaries provide a comprehensive look at safety data early in the product's post-approval life cycle and are based on reports by manufacturers, providers, consumers and others to the FDA's Adverse Event Reporting System (AERS) and the Vaccine Adverse Event Reporting System maintained by the FDA and the Center for Disease Control and Prevention; periodic safety information submitted to FDA by manufacturers; information contained in the medical literature; and data from ongoing drug and biologic studies.

Included in the summaries may be information on potentially serious, previously unidentified risks, if any are found during the review, as well as known adverse events that occur more often than they did during clinical studies. The summaries will also include a brief discussion of any steps FDA may be taking to address these safety issues.

Under Section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA), FDA is required to prepare the safety summaries within 18 months after a product's approval or after it has been used by 10,000 patients, whichever comes later.

"Conducting systematic, comprehensive, safety reviews of recently approved drugs and biologics provides an early detection mechanism for potentially serious risks and complements the FDA's analysis of safety data during drug development and the agency's routine monitoring of safety information after product approval," said Gerald Dal Pan, M.D., M.H.S., director of the Office of Surveillance and Epidemiology in the FDA's Center for Drug Evaluation and Research.

"These summaries will provide clear and useful information in a timely manner that can be used by providers and patients to make informed decisions about an individual's health," said Robert Ball, M.D., M.P.H., Sc.M., director of the Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research.

Initial summary reports will contain information on drugs and biologics approved since September 2007, including several drugs for infections, hypertension, depression and other conditions. The summary reports will be located on an FDA Web page that was first established in 2008 to serve as a portal for drug safety information.

Prasugrel

Prasugrel (marketing name Effient in the US, Efient in EU and Prasita in India) is a novel platelet inhibitor developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). Prasugrel was approved for use in Europe in February 2009, and is currently available in the UK. On July 10, 2009, the US Food and Drug Administration approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI.
Pharmacology:

Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y₁₂ receptors. Compared to clopidogrel, "prasugrel(trade name apagrel) inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI". Unlike clopidogrel, which was issued a black box warning from the FDA on March 12, 2010, .prasugrel has not been shown to carry those same limitations.

Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60-mg loading dose of Effient. Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

Pharmacokinetics:

Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.

ABSORPTION AND BINDING - Following an oral administration, ≥ 79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (C_max) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but C_max was decreased by 49% and T_max was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.

METABOLISM AND ELIMINATION - Prasugrel is not detected in plasma after oral administration. It is rapidly hydrolyzed in the intestine to a thialactone, which is then converted to the active metabolite by a single step, primarily by the CYP3A4 and CYP2B6 and to a lesser extent by the CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabloite range from 44 to 68 L and the estimates of apparent clearance range from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolite.

DRUG INTERACTIONS

Potential for Other Drugs to Affect Prasugrel

Inhibitors of CYP3A - Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and Tmax, but decreased the Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel.

Inducers of Cytochromes P450 - Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel.

Drugs that Elevate Gastric pH - Daily coadministration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) decreased the Cmax of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and Tmax. In TRITON-TIMI 38, Effient was administered without regard to coadministration of a proton pump inhibitor or H2 blocker.

Statins - Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

Heparin - A single intravenous dose of unfractionated heparin (100 U/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone.

Aspirin - Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone.

Warfarin - A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin.

Potential for Prasugrel to Affect Other Drugs

In vitro metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.

Drugs Metabolized by CYP2B6 — Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinical significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.

Effect on Digoxin - The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration.

Pharmacogenomics

There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.
TRITON-TIMI 38 study

As published in the New England Journal of Medicine's online edition, the TRITON-TIMI 38 study of 13,608 patients with acute coronary syndromes compared prasugrel against clopidogrel, both in combination with aspirin, and found that, as a more potent anti-platelet agent, prasugrel reduced the combined rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (12.1% for clopidogrel vs. 9.9% for prasugrel). This difference in the primary endpoint was mainly driven by the reduction of non-fatal myocardial infarctions. However, an increased rate of serious bleedings (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleedings (0.4% vs. 0.1%) was also observed. Overall mortality did not differ between the two treatment groups.

From the editorial in the NEJM, "In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel".

In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), prasugrel was associated with a significantly lower incidence of ischemic events than clopidogrel, and was particularly effective in specific subgroups of patients, such as those with diabetes mellitus. In this sub-group there is a 30% relative risk reduction (4.2% ARR for unstable angina/NSTEMI and 5% AAR for STEMI) compared to the clopidogrel group without significant increased risk for major bleeding(2.2% vs. 2.3%). However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60>

Ranbaxy Launches Antiplatelet Agent Prasugrel in India

Daiichi Sankyo Company Limited ("Daiichi Sankyo") and Ranbaxy Laboratories Limited ("Ranbaxy") announced today that Ranbaxy has launched a generic version of prasugrel in India. The product, called Prasita, is an antiplatelet agent for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Prasita is solely marketed by Ranbaxy in India.

Following the April 2009 launch of Olvance (olmesartan medoxomil), an antihypertensive originally discovered by Daiichi Sankyo, Prasita is the second product from the Daiichi Sankyo portfolio to be introduced in India through the strong Ranbaxy business network. Ranbaxy will create awareness, understanding and acceptance of the new antiplatelet therapy among the target audiences in the country.

"We are pleased to be able to introduce Prasita in India," said Atul Sobti, CEO and Managing Director of Ranbaxy. "A number of synergy projects between Ranbaxy and Daiichi Sankyo are already underway, and we will further strengthen our common endeavour to realize greater benefits from our Hybrid Business Model."

"The launch of our two top flagship products, olmesartan medoxomil and prasugrel, by Ranbaxy shows our serious commitment to India, and we will continue to explore further collaborations leveraging the Hybrid Business Model," said Takashi Shoda, President & CEO of Daiichi Sankyo.

About Daiichi Sankyo
The Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of patients in both mature and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial infections, the Group is engaged in the development of treatments for thrombotic disorders and focused on the discovery of novel oncology and cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has created a "Hybrid Business Model," which will respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit www.daiichisankyo.com.

About Ranbaxy Laboratories Limited
Ranbaxy Laboratories Limited, India's largest pharmaceutical company, is an integrated, research based, international pharmaceutical company producing a wide range of quality, affordable generic medicines, trusted by healthcare professionals and patients across geographies. Ranbaxy’s continued focus on R&D has resulted in several approvals in developed markets and significant progress in New Drug Discovery Research. The Company’s foray into Novel Drug Delivery Systems has led to proprietary "platform technologies," resulting in a number of products under development. The Company is serving its customers in over 125 countries and has an expanding international portfolio of affiliates, joint ventures and alliances, ground operations in 46 countries and manufacturing operations in 7 countries. Ranbaxy is a member of the Daiichi Sankyo Group. Daiichi Sankyo is a leading global pharma innovator, headquartered in Tokyo, Japan.