Share your Favorite Biotech/Pharma/Medicine/Clinical Trials articles on Your Helix!-Professional Networking Site Designed for Biotech/Pharma Community:

Your Helix !





Your Ad Here

Results from First Prospective Study to Examine Skin Toxicities in Metastatic Colorectal Cancer (mCRC) Patients Receiving Epidermal Growth Factor Receptor (EGFr)
 

-Study Adds to Body of Evidence on KRAS Mutational Status As a Predictive Biomarker of Vectibix Response-

 

BARCELONA, Spain-- June 26, 2008--Amgen announced updated results from the STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) trial, the first prospective study to examine differences between preemptive and reactive skin treatment for skin toxicities in metastatic colorectal cancer (mCRC) patients receiving epidermal growth factor receptor (EGFr) therapy. The analysis found that preemptive treatment reduced the incidence rate of grade 2 and greater skin toxicities by over 50 percent without additional side effects when compared to reactive skin treatment. The incidence of grade 3 or greater skin toxicities were 62 percent and 29 percent in the reactive and preemptive treatment groups respectively (odds ratio (95 percent CI): 0.3 (0.1. 0.6)). These data were presented at the 10th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

 

In this patient population, the time to severe skin toxicity was significantly delayed by preemptive skin treatment; at 6 weeks the event- (grade 2 or greater skin toxicity) free probabilities were 70 percent and 38 percent for the preemptive and reactive arms respectively (difference: 32.2 percent (95 percent CI: 12.8, 51.7) in favor of the preemptive arm). Time-to-first-occurrence of any specific grade 2 or higher skin toxicity was also significantly delayed in the preemptive arm. The estimated median time to the first occurrence was 2.7 weeks (95 percent CI: 2.1, 6.3) in the reactive arm and it was not reached in the preemptive arm.

 

Skin toxicity, or rash, is one of the most common side effects of EGFr inhibitors like Vectibix(R) (panitumumab). The secondary endpoints were safety and efficacy and the analysis included data from 95 patients who had the opportunity to complete 14 weeks on study. Consistent with previous results, analyses by KRAS favored the wild-type group for all efficacy endpoints.

 

Since skin rash is the most common side effect of EGFr therapy, the results of the STEPP trial showing that skin rash may be controlled by a relatively simple preemptive treatment, represent a significant advancement, said David Chang, M.D., vice president for oncology clinical development at Amgen. In addition, these data add to the growing body of evidence supporting the utility of Vectibix in combination with chemotherapy for patients with wild-type KRAS tumors.

 

About STEPP

Patients enrolled in STEPP received, at the discretion of the investigator, either second-line FOLFIRI-based chemotherapy plus 6.0 mg/kg of Vectibix every two weeks (Q2W) or irinotecan-based chemotherapy plus 9.0 mg/kg Vectibix every three weeks (Q3W) and were randomized to preemptive or reactive skin treatment. Preemptive skin treatment included the administration of skin moisturizer, sunscreen, topical steroid and oral doxycycline. The primary endpoint was the incidence of grade two or greater skin toxicities during the six-week skin treatment period. Secondary endpoints included safety and efficacy.

 

The analysis of 95 patients showed the following adverse events (AE): 93 percent of all patients had a Vectibix treatment-related AE; 71 percent of all patients had a grade 3/4 AE. Vectibix dose reductions due to skin toxicities occurred in eight percent of patients. Serious adverse events (SAE) were observed in 38 percent of patients and AEs caused 14 percent of patients to end treatment.

 

About Vectibix

 Vectibix is U.S. Food and Drug Administration (FDA) approved as a monotherapy for the treatment of patients with EGFr- expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix as a single agent for the treatment of EGFr-expressing, mCRC is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

 

In December 2007, the European Medicines Agency (EMEA) granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFr-expressing mCRC with non-mutated (wild-type) KRAS genes after failure of standard chemotherapy regimens. Vectibix is now available in 11 European countries. In the first half of 2008 Vectibix was approved by health authorities in Canada and Australia.

 

Important Product Safety Information - EU

 Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 90 percent) treated with Vectibix. The majority of dermatological reactions are mild to moderate in nature. In clinical studies, subsequent to the development of severe dermatological reactions (including sore mouth), infectious complications including sepsis, in rare cases leading to death, and local abscesses requiring incisions and drainage were reported. Patients who have severe dermatologic reactions or who develop worsening reactions whilst receiving Vectibix should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment promptly initiated. Severe infusion reactions occurred with Vectibix in approximately one percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and / or persistence of the reaction.

 

Important Product Safety Information - US

 Dermatologic toxicities, related to Vectibix blockade of EGF binding and subsequent inhibition of EGF receptor-mediated signaling pathways, included but were not limited to dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Dermatologic toxicities were reported in 89 percent of patients treated with Vectibix and were severe in 12 percent of patients. Severe dermatologic toxicities were complicated by infection, including sepsis, septic death, and abscesses requiring incisions and drainage. Vectibix may need to be withheld or discontinued for severe dermatologic toxicities.

 

Severe infusion reactions occurred with Vectibix in approximately 1 percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and/or persistence of the reaction.

 

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.

 

Source: Amgen Press Release

 

Genentech’s Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in Women With Advanced HER2-Negative Breast Cancer
 

-- Positive AVADO Results Support Efficacy and Safety of Avastin in First-Line Metastatic Breast Cancer  --

 

Chicago --May 31, 2008--  Genentech, Inc. announced that Avastin® (bevacizumab), in combination with docetaxel chemotherapy, significantly increased the time women with metastatic breast cancer receiving first-line therapy lived without their disease advancing, as defined by the primary endpoint of progression-free survival (PFS). In this Roche-sponsored, placebo-controlled Phase III trial (AVADO), two dose levels of Avastin in combination with docetaxel chemotherapy showed a statistically significant improvement in PFS compared to docetaxel chemotherapy alone, according to an investigator-assessed analysis. No new safety signals for Avastin were observed in the study.

The results were featured today during a press briefing at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) and will be presented tomorrow by David Miles, M.D., medical oncologist, Mount Vernon Hospital, United Kingdom (Abstract # LBA1011 – June 1, 2008 at 8:30 a.m. CDT in E Hall D1).

 

"These results build upon previous data and expand our understanding of Avastin’s efficacy and safety when combined with another commonly used taxane chemotherapy," said Dr. David Miles, principal investigator of the study. "Importantly, this study supports that Avastin can be used with taxane-based chemotherapy to provide a meaningful benefit for patients with advanced HER2-negative breast cancer."

 

Genentech is required to submit to the U.S. Food and Drug Administration (FDA) by mid-2009 the results of AVADO and RIBBON I, a third Phase III study in first-line metastatic breast cancer. Results for the RIBBON I study are expected later this year.

 

The pre-specified analysis of AVADO for U.S. regulatory purposes showed that Avastin combined with chemotherapy improved PFS by up to 64 percent (hazard ratio of 0.61; p<0.0001) in the 15 mg/kg treatment arm and by up to 45 percent (hazard ratio of 0.69; p=0.0035) in the 7.5 mg/kg treatment arm, compared to chemotherapy alone. Overall response rate, a secondary endpoint, was also positive and supported the PFS benefit observed in this study. After one year, 83 percent and 78 percent of patients were alive in the 15 mg/kg and 7.5 mg/kg Avastin treatment arms, compared to 73 percent of patients receiving chemotherapy alone.

 

"The totality of the AVADO results, including positive primary and secondary endpoints and reassurances of safety, support the benefit of Avastin in extending the time women lived without their disease progressing when combined with chemotherapy as a first-line treatment," said Susan Desmond-Hellmann, M.D., M.P.H., president, Product Development. "We are committed to fully evaluating Avastin’s efficacy and safety in metastatic breast cancer and anticipate the results of a third Phase III trial later this year."

 

About AVADO

AVADO was an international, multicenter, randomized, double-blind, placebo-controlled clinical trial that enrolled 736 patients with locally recurrent or metastatic HER2-negative breast cancer who had not received chemotherapy for their metastatic disease. Patients were randomized to one of two doses of Avastin (15 mg/kg or 7.5 mg/kg) or placebo given every three weeks in combination with docetaxel chemotherapy for a maximum of nine cycles. Patients discontinuing docetaxel for toxicity or after nine cycles were to continue on Avastin only or placebo until disease progression. The AVADO study was not designed to compare the two dose levels of Avastin.

 

In the 15 mg/kg and 7.5 mg/kg Avastin treatment arms, the 64 percent and 45 percent improvements in PFS observed can also be referred to as 39 percent and 31 percent reductions in the risk of cancer progression or death. Median PFS was 8.8 months, 8.7 months and 8.0 months in the 15 mg/kg and 7.5 mg/kg Avastin plus chemotherapy arms and the chemotherapy alone arm, respectively. Overall response rates were 63 percent (p=0.0001) and 55 percent (p=0.0295) in the 15 mg/kg and 7.5 mg/kg Avastin plus chemotherapy arms, compared to 44 percent in the chemotherapy alone arm.

 

The study protocol specified analyses for overall survival at the time of primary endpoint analysis and 24 months after the last patient was enrolled. The final analysis for overall survival is expected in 2009. Hazard ratios for the preliminary analysis of overall survival are 0.68 and 0.92 for the 15 mg/kg and 7.5 mg/kg Avastin arms, respectively. These initial results for overall survival are not statistically significant and are based on early information.

 

Efficacy Results

15 mg/kg Avastin + docetaxel1

7.5 mg/kg Avastin + docetaxel1

Placebo +
docetaxel1

Progression-Free Survival (PFS)2

     Overall PFS
     Improvement
     Risk Reduction
     Hazard Ratio
     p-value





64%
39%
0.61
p<0.0001





45%
31%
0.69
p=0.0035







N/A

Median PFS (months)

8.8

8.7

8.0

Overall Response Rate (%)3

p-value

63

p=0.0001

55

p=0.0295

44

1-Year Survival Rate (%)

83

78

73

Overall Survival (not mature)

Hazard Ratio



0.68



0.92



N/A

 

1 Each Avastin + docetaxel arm was studied against placebo + docetaxel. The study was not designed to compare the two Avastin arms.

2 Pre-specified primary endpoint analysis for U.S. regulatory purposes.

3 Among patients with measurable disease at baseline.

 

The AVADO study provided a comprehensive safety assessment of the Avastin and docetaxel combination by using a placebo control arm and collecting Grade 1 to 5 adverse events in all arms of the study. The most common severe adverse events were generally consistent with those observed in a previous Phase III study of Avastin in metastatic breast cancer.

 

Safety Results
% (n)

15 mg/kg Avastin
+ docetaxel

7.5 mg/kg Avastin
+ docetaxel

Placebo
+ docetaxel

Grade 3-5 Adverse Events (AEs)

74% (183/247)

75% (187/250)

67% (156/233)

≥Grade 3 Hypertension

3.2% (8/247)

0.4% (1/250)

1.3% (3/233)

≥Grade 3 Febrile neutropenia

16.6% (41/247)

15.2% (38/250)

12.0% (28/233)

≥Grade 3 Skin exfoliation

1.2% (3/247)

2.4% (6/250)

0% (0/233)

≥Grade 3 Mucosal inflammation

4.9% (12/247)

4.0% (10/250)

0.4% (1/233)

Grade 5 AEs (deaths during blinded study treatment not due to breast cancer)

1.6% (4/247)

1.6% (4/250)

2.6% (6/233)

 

 

About Breast Cancer

Breast cancer is the second most common form of cancer and second leading cause of cancer deaths among American women. According to the American Cancer Society, an estimated 182,000 women will be diagnosed with breast cancer and approximately 40,000 will die from the disease in the U.S. in 2008. Genentech estimates that 75 percent of women with newly diagnosed metastatic breast cancer are HER2-negative.

 

About Avastin

Avastin is a therapeutic antibody designed to specifically inhibit vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis and the maintenance of existing blood vessels throughout the lifecycle of a tumor. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body (metastasize).

 

Avastin is indicated for the first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy, and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. For more information on angiogenesis, visit http://www.gene.com. For full Prescribing Information and Boxed Warnings on Avastin, visit http://www.avastin.com.

 

Avastin Safety

Avastin has a well-characterized safety profile in its approved indications. The most serious adverse events associated with Avastin across all trials were gastrointestinal perforation, wound healing complications, hemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome (RPLS), neutropenia and infection, nephrotic syndrome and congestive heart failure.

 

The most common severe adverse reactions (NCI-CTC Grade 3-5) across clinical trials in metastatic colorectal cancer, NSCLC, and metastatic breast cancer that occurred at a higher incidence (greater than or equal to 2 percent higher rate vs. controls) were hypertension, proteinuria and headache.

 

About Genentech

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines for patients with significant unmet medical needs. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com.

 

Source: Genentech Press Release

Results from PhaseI/II Clinical Trials for Enhanze Technology™ GAMMAGARD LIQUID Administered Subcutaneously
 

Phase I/II data showed that Enhanze Technology™ enabled subcutaneous administration of a monthly dose of GAMMAGARD LIQUID in patients with Primary Immunodeficiency

 

PHILADELPHIA, Pa., March  2008 – Baxter International Inc. announced the preliminary results of a Phase I/II clinical trial, in which subcutaneous infusion (under the skin) of GAMMAGARD LIQUID [Immune Globulin Intravenous (Human)] (IGIV) with Enhanze™ Technology enabled administration of a full monthly dose via a single site to patients with primary immunodeficiency (PID). The results were presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) in Philadelphia, PA.

 

 GAMMAGARD LIQUID is approved for intravenous administration, which due to large infusion volumes of the therapy needing to be delivered, can take several hours once a month at a doctor’s office or hospital. By contrast, subcutaneous administration of IGIV has been limited by the inability of the tissue to absorb large volumes of injected drugs, creating the need to administer the therapy in smaller, weekly doses and through multiple injection sites. Subcutaneous administration of GAMMAGARD LIQUID with Enhanze Technology via a single site could allow patients to administer a sufficient dose of IGIV once monthly at home.

 

 In the Phase I/II trial, 10 of the 11 patients studied received monthly doses of subcutaneously administered GAMMAGARD LIQUID with Enhanze Technology of 25.5 to 61.2 grams (255 to 612 mL) in a single site. All patients in the trial received the therapy at infusion rates between 120 mL/hr to 300 mL/hr, similar to infusion rates for intravenous administration. The average bioavailability of the subcutaneously administered combination of GAMMAGARD LIQUID with Enhanze Technology was 92 percent of the traditional, monthly intravenous administration.

 

“These early results are the latest demonstration of Baxter’s ongoing commitment to innovation and, in particular, to advancing the science of IGIV therapy,” said Hartmut J. Ehrlich, MD, vice president of Global Research and Development for Baxter’s BioScience business. “While further studies are required to confirm these results, Baxter plans to initiate a pivotal Phase III trial using GAMMAGARD LIQUID with Enhanze Technology pending discussions with regulatory authorities by the beginning of 2009.”

 

Phase I/II Trial Design and Results

 The Phase I/II clinical trial was the result of an agreement between Baxter and Halozyme Therapeutics, Inc., under which Halozyme’s proprietary Enhanze Technology was applied to the development of a subcutaneous route of administration for GAMMAGARD LIQUID.

 

 Halozyme’s Enhanze Technology is based on recombinant human hyaluronidase (rHuPH20), which facilitates dispersion and absorption of subcutaneously injected solutions. The Phase I/II trial evaluated the safety, tolerability and pharmacokinetics of a monthly subcutaneous administration of GAMMAGARD LIQUID with Enhanze Technology in 11 PID patients in the United States. The patients were infused with varying amounts of rHuPH20 with one-, two-, three- and then four-week doses of GAMMAGARD LIQUID to determine the amount of enzyme required to enable a full monthly dose to be infused in a single site at rates equivalent to those administered in intravenous infusions. The trial also evaluated the effect of rHuPH20 on the bioavailability of GAMMAGARD LIQUID administered subcutaneously compared to intravenously.

 

 One patient withdrew from the study, citing moderate discomfort with the one-week dose, while the 10 patients who completed the study experienced mild local reactions that were not dose-limiting, such as swelling and redness. No drug-related allergic reactions occurred. Administration time and flow rates were limited by pump characteristics and not by patient discomfort.

 

 

Phase III Trial for Subcutaneous Administration of GAMMAGARD LIQUID

 In addition to the announcement of results for the Phase I/II for GAMMAGARD LIQUID and Enhanze Technology, Baxter also announced the initiation of a pivotal Phase III trial of subcutaneous administration of GAMMAGARD LIQUID alone. The Phase III trial will evaluate the bioavailability of GAMMAGARD LIQUID after administration intravenously, subcutaneously or subcutaneously at an adapted dose, as measured by the area under the curve of IgG concentration vs. time curve per week. Final results of the study are expected to become available in 2009.

 

 

 About Enhanze Technology

 Enhanze Technology is Halozyme's proprietary drug delivery technology based on rHuPH20, a recombinant form of hyaluronidase, a naturally occurring human enzyme. The rHuPH20 mechanism of action is its ability to temporarily break down hyaluronic acid, the space-filling "gel"-like substance that is a major component of subcutaneous tissues. When combined or co-formulated with certain injectable drugs, Enhanze Technology may facilitate the absorption and dispersion of these drugs by temporarily clearing a path through connective tissue. Molecules as large as 200 nanometers may pass freely through the perforated extracellular matrix, which recovers its normal density in 48 hours, leading to a drug delivery platform that does not permanently alter the architecture of the tissue.

 

 

About Primary Immunodeficiency Disorders

Primary immunodeficiency disorders encompass more than 100 diseases caused by an immune system that does not function correctly. According to the Immune Deficiency Foundation, approximately 50,000 persons in the United States have one of the primary immunodeficiency disorders. For many people with primary immunodeficiency, the cause is a lack of antibodies. IGIV therapy can help restore IgG levels to near normal, helping the immune system function properly and prevent infections or fight them when they occur.

 

 About GAMMAGARD LIQUID™ 10%

 GAMMAGARD LIQUID 10% (known as KIOVIG™ in Europe) is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. These include but are not limited to congenital X-linked agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

 

 

Important Safety Information

 

GAMMAGARD LIQUID

 GAMMAGARD LIQUID is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to Immune Globulin (Human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction.

 

Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number.

 

Glycine, an amino acid, is used as a stabilizer. GAMMAGARD LIQUID does not contain sucrose.

 

GAMMAGARD LIQUID is made from human plasma. It may carry a risk of transmitting infectious agents, viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

 

 Components used in the packaging of this product are latex-free.

 

 Thrombotic events have been reported in association with IGIV. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoagulable disorders, and prolonged periods of immobilization.

 

 IGIV products can contain blood group antibodies that may cause a positive direct antiglobulin reaction and, rarely, hemolysis.

 

 Aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

 

Various mild and moderate reactions, such as headache, fever, fatigue, chills, flushing, dizziness, urticaria, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, muscle cramps, and changes in blood pressure may occur with infusions of Immune Globulin Intravenous (Human).

 

For full prescribing information, please visit http://www.gammagardliquid.com.

 

 

About Baxter International Inc.

Baxter International Inc., through its subsidiaries, assists healthcare professionals and their patients with the treatment of complex medical conditions, including hemophilia, immune disorders, cancer, infectious diseases, kidney disease, trauma and other conditions. The company applies its expertise in medical devices, pharmaceuticals and biotechnology to make a meaningful difference in patients' lives.

 

 About Halozyme Therapeutics, Inc.

Halozyme is a biopharmaceutical company developing and commercializing products based on the extracellular matrix for the drug delivery, oncology, and dermatology markets. The company's portfolio of products is based on intellectual property covering the family of human enzymes known as hyaluronidases. The company's Enhanze Technology is a novel drug delivery platform designed to increase the absorption and dispersion of biologics. In addition, the company received FDA approval for two products: Cumulase® and HYLENEX, for use as an adjuvant to increase the absorption and dispersion of other injected drugs and fluids. The company also has a number of different enzymes in its portfolio that are targeting significant areas of unmet need.

 

 GAMMAGARD LIQUID and KIOVIG are trademarks of Baxter Healthcare Corporation.

 

 Enhanze is a trademark of Halozyme Therapeutics, Inc.

 

Source: Baxter Press Release

 

Share your Favorite Biotech/Pharma/Medicine/Clinical Trials articles on Your Helix!-Professional Networking Site Designed for Biotech/Pharma Community:

Your Helix !


FDA Approves ISENTRESS™ (Raltegravir) Tablets, First-in-Class Oral HIV-1 Integrase Inhibitor
 

October 2007 - Merck & Co., Inc., announced that the U.S. Food and Drug Administration (FDA) granted ISENTRESS™ (raltegravir) tablets accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

 

This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS [pronounced i-sen-tris].  These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults.  The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.  The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients.  There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.  Longer term data will be required before the FDA can consider traditional approval for ISENTRESS.

 

ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors.  ISENTRESS works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme.  Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells.  There are drugs in use that inhibit two other enzymes critical to the HIV replication process - protease and reverse transcriptase - but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

 

The FDA's decision was based on a 24-week analysis of clinical trials in which ISENTRESS in combination with optimized background therapy (OBT) in treatment-experienced patients, provided significant reductions in HIV RNA viral load and increases in CD4 cell counts.

 

"The development of ISENTRESS is a significant milestone in the history of HIV/AIDS therapy because we now have a drug that's potent against another key enzyme essential for viral replication," said Joseph J. Eron Jr., M.D., professor of medicine, Division of Infectious Diseases, UNC Chapel Hill School of Medicine.  "It's important for physicians to know that ISENTRESS should always be used in combination with other active agents."

 

Data from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral therapies showed that ISENTRESS 400 mg dosed twice daily in combination with OBT was significantly more effective at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these patients living with HIV, when compared to a regimen of placebo plus OBT.

 

Pooled analyses from the two Phase III studies showed that after 24 weeks of therapy, 75.5 percent of patients (216 out of 286) receiving ISENTRESS in combination with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to 39.3 percent of patients (59 out of 150) receiving placebo plus OBT.  In addition, after 24 weeks of therapy, 62.6 percent of patients (179 out of 286) receiving ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to 33.3 percent of patients (50 out of 150) receiving placebo plus OBT.  After 24 weeks of therapy, increases in CD4 cell counts from baseline were 89 and 35 cells/mm3 for patients receiving ISENTRESS plus OBT and for those receiving placebo plus OBT, respectively.

 

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

 

The most commonly reported adverse experiences of any severity (mild, moderate or severe) regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

 

Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known.  ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

 

Safety and tolerability profile of ISENTRESS

Results from pooled safety analyses from three separate studies in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT.  In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

 

Drug interactions

Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes.  Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS.

 

About ISENTRESS

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

 

Merck has worked closely with the HIV community regarding the price of ISENTRESS.  The wholesale acquisition cost (WAC) of ISENTRESS will be $27 per day, comparable to the price of several available ritonavir-boosted protease inhibitors.

 

To help patients in the United States who cannot afford treatment with ISENTRESS, the SUPPORT™ program is available.  The SUPPORT program is a patient assistance program to help patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues.  In addition, Merck also participates in the Partnership for Prescription Assistance program, a single point of access to more than 475 public and private patient assistance programs.  ISENTRESS will be available in pharmacies in approximately two weeks.  For more information on ISENTRESS, visit www.isentress.com.

 

Expanded access program

ISENTRESS is currently available worldwide to qualified patients through an expanded access clinical research program, EARMRK.  This global program provides early access to ISENTRESS for patients failing current therapy whose HIV is resistant to drugs in three existing classes (NRTIs, NNRTIs, PIs) of antiretroviral medications.  Information about the program can be found at www.benchmrk.com.

 

Merck HIV research

Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases - including HIV.  Merck's efforts to develop investigational treatments for HIV/AIDS have been under way for more than 20 years and continue today.  Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.

 

Prevalence of HIV/AIDS

In 2006, over one million Americans were living with HIV/AIDS and it is estimated that approximately 40,000 new cases of HIV/AIDS are diagnosed each year in the United States. Worldwide, an estimated 40 million people are infected with HIV/AIDS, and more than four million new infections occurred in 2006.

 

"As the AIDS crisis continues, new drugs like ISENTRESS are needed, which target the virus in unique ways," said Ben Cheng, deputy director, Forum for Collaborative HIV Research.  "The HIV Advocacy Community is really excited and encouraged by this new treatment."

 

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit www.merck.com.

 

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed, and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

 

ISENTRESS™ is a trademark of Merck & Co., Inc.

SUPPORT™ is a trademark of Merck & Co., Inc. 

Share your Favorite articles on the following Social Networks:

Share on Facebook StumbleUpon Digg!



Largest Cervical Cancer Vaccine Efficacy Trial Shows Cervarix™ Provides Excellent Protection Against Lesions Caused by Most Common Cancer-causing Virus Types
 

----Results also show significant additional protection against infection with virus types beyond 16 and 18 with the GSK cervical cancer candidate vaccine----

 

27 June 2007 — LONDON — Results from an interim analysis of a Phase III study show that CervarixTM, the GlaxoSmithKline (GSK) cervical cancer candidate vaccine, provides up to 100 percent protection against advanced precancerous lesions caused by the most common types of human papillomavirus, types 16 and 18. The study also strengthens earlier preliminary evidence that the vaccine provides significant protection against infection with additional cancer-causing virus types. These results were published today in The Lancet.

 

 “This landmark trial has provided important new insights into the natural history of cervical lesions, and helps us to more clearly understand the causal link between these lesions and the virus types detected within them,” said Gary Dubin, M.D., Vice President, North American Clinical Development, GSK.

 

 “These results validate our previous clinical findings, and we believe that the data in this study show the GSK candidate vaccine provided 100 percent protection against precancerous lesions caused by virus types 16 and 18, which are responsible for 70 percent of all cervical cancers,” commented David Stout, President of Pharmaceuticals Operations, GSK.

 

 In this study, the majority of precancerous lesions included in the primary analysis had multiple cancer-causing virus types detected, making it difficult to clearly determine which virus type was the cause of the lesion. The observation of such a high number of lesions with multiple virus types was not expected based on published data. This necessitated additional analyses to determine which virus type was the cause of the lesion. In these analyses, causality was determined by confirming the presence of the virus in both the lesion and in previous Pap smear samples.

 

When using the pre-specified analyses which only required detection of virus in the lesion, and not taking previous samples into account, vaccine efficacy in women with virus type 16 and/or 18 in the lesion was 90 percent. When considering the virus type present in both the lesion and previous samples, the vaccine was 100 percent effective in preventing precancerous lesions caused by virus types 16 and/or 18.

 

“The findings are very encouraging because the women in the study are representative of the patients seen by physicians every day in their practice,” said lead investigator Professor Jorma Paavonen, Department of Obstetrics and Gynecology at Helsinki University Central Hospital, Finland. “This provides a strong indication that this vaccine can protect women from the infections that may develop into cervical cancer.”

 

 This pivotal, Phase III study involves 18,644 women aged 15-25 from 14 countries across Europe, Asia-Pacific and Latin and North America, making it the single largest cervical cancer vaccine efficacy trial to date.

 

 

Cross Protection

In this clinical trial, the vaccine showed significant cross-protection against 6-month persistent infection caused by virus types 45, 31 and 52. Together with virus types 16 and 18, these types are collectively responsible for more than 80 percent of cervical cancer cases globally.

 

“These results suggest protection from persistent infection with additional cancer-causing virus types beyond those contained in the vaccine,” said Professor Margaret Stanley, Pathology Department, University of Cambridge, UK. “This is important becausepersistent infection is a necessary first step in the development of precancerous lesions and cervical cancers.”

 

The data also shows that the GSK candidate vaccine, formulated with the innovative adjuvant system AS04, produced a robust immune response for both virus types 16 and 18. This strong immune response has been shown to persist for up to 5.5 years in previous studies.

 

As in previous studies conducted over the past five years and involving over 40,000 women, the candidate vaccine has been shown to be generally well-tolerated.

 

 

About the Study

These data are interim results from an ongoing Phase III randomised, controlled trial of 18,644 women aged between 15-25 years of age from across four continents — Asia-Pacific, Europe, Latin America and North America, in a total of 14 countries.

 

This interim analysis shows results over an average follow-up time of 15 months after first vaccination, in which a proportion of the women enrolled already had a human papillomavirus infection or abnormal cytology (abnormal Pap smears) at study entry.

 

The primary objective of the interim analysis was to evaluate the vaccine efficacy against precancerous lesions associated with cancer-causing virus types 16 and 18 among women who were DNA-negative and seronegative for the corresponding vaccine type at study entry. Secondary objectives included efficacy against 6- and 12-month persistent infection with virus types 16, 18 or other cancer-causing virus types, immunogenicity and safety.

 

 

About the GSK Cervical Cancer Vaccine

In May, CervarixTM was granted its first licence in a major market by the Therapeutic Goods Administration (TGA) of Australia for the prevention of cervical cancer and precancerous lesions caused by human papillomavirus types 16 and 18 for use in females ages 10 to 45 years. This is the first time that a cervical cancer vaccine has been explicitly indicated anywhere in the world for women over the age of 26.

 

GSK submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for its cervical cancer candidate vaccine in March 2007, following earlier regulatory filings with the European Medicines Agency (EMEA) and regulatory filings in Africa, Asia and Latin America.

 

 

About Cervical Cancer

Worldwide, more than 500,000 women will be newly diagnosed with cervical cancer and over 280,000 women will die from it each year. In the United States, after breast cancer, cervical cancer is the leading cause of cancer death in women ages 20-39.Cervical cancer and precancerous lesions are a major health, psychological and social burden on women everywhere.

 

Published data shows that any given time, only 2.3 percent of women ages 14-59 are currently infected with cancer-causing human papillomavirus types 16 and 18. Only 0.1 percent are currently infected with both types. Therefore, the vast majority of these women (up to 99.9 percent) may benefit from vaccination as they are not actively infected with these virus types and are potentially at risk for developing an infection in the future. Naturally occurring infections with cancer-causing virus types may resolve on their own, but this previous exposure may not protect against future infections with the same virus types. Some infections persist and develop into precancerous lesions, which can advance into cancer.

 

 

About GlaxoSmithKline

GlaxoSmithKline–one of the world’s leading research-based pharmaceutical and healthcare companies–is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information, please visit www.gsk.com/media.

 

GSK Biologicals (GSK Bio), one of the world’s leading vaccine manufacturers, is headquartered in Rixensart, Belgium, where the majority of GlaxoSmithKline’s activities in the field of vaccine research, development and production are conducted. GSK Bio employs more than 1,500 scientists, who are devoted to discovering new vaccines and developing more cost-effective and convenient combination products to prevent infections that cause serious medical problems worldwide. In 2006, GSK Bio distributed more than 1.1 billion doses of vaccines to 169 countries in both the developed and the developing world — an average of 3 million doses a day. Of those vaccine doses, approximately 136 million were doses of combination paediatric vaccines which protect the world’s children from up to six diseases in one vaccine.

 

Cervarix is a trademark of the GlaxoSmithKline group of companies.

 

Source: GSK Press Release

 

 

Lipitor Provides Unprecedented Cardiovascular Risk Reductions in Diabetes Patients with Metabolic Syndrome and in Stroke Patients
 

--Lipitor is the Only Statin to Have Been Studied Solely in Patients with Recent Stroke or Mini-stroke--

 

March 26, 2007. NEW ORLEANS--(BUSINESS WIRE)--Pfizer announced today that Lipitor® (atorvastatin calcium) Tablets 10 mg provided a significant 61 percent reduction in stroke in patients with type 2 diabetes and metabolic syndrome but without heart disease. In a separate study, patients who had suffered a recurrent stroke or mini-stroke during the trial had a significant 53 percent reduction in the risk of major coronary events (death from cardiac causes, heart attack, or resuscitation after cardiac arrest) with Lipitor 80 mg. These analyses from two landmark clinical outcomes studies were presented at the annual meeting of the American College of Cardiology.

 

“What’s impressive is the magnitude of cardiovascular efficacy, including a 61 percent reduction in the risk of stroke, that Lipitor offered these patients who were at high risk for cardiovascular events,” said Professor John Betteridge, a lead author of CARDS and professor of endocrinology and metabolism at University College London Hospital.

 

“These results add to the unique and robust body of evidence for Lipitor that includes proven reductions in heart attacks and strokes, impressive average LDL lowering of 39 percent to 60 percent, and an established safety profile across a broad range of patients,” said Dr. Michael Berelowitz, senior vice president of Pfizer’s global medical division.

 

New Analysis of the Collaborative Atorvastatin Diabetes Study (CARDS)

 

In a new analysis of more than 2,200 patients with type 2 diabetes who met the criteria for metabolic syndrome in CARDS:

 

Lipitor 10 mg provided a significant 41 percent reduction in the risk of major cardiovascular events (death from coronary heart disease, heart attacks, strokes, certain types of heart surgery, chest pain) compared with placebo.

Lipitor 10 mg provided a significant 61 percent reduction in the risk of stroke compared with placebo.

 

About Metabolic Syndrome

 

Metabolic syndrome was defined in this analysis using the International Diabetes Federation criteria of central obesity and two or more of the following conditions: diabetes, treated hypertension or high blood pressure, high triglyceride and low levels of good cholesterol (HDL).

 

Nearly 47 million Americans currently live with metabolic syndrome according to the American Heart Association. According to the International Diabetes Foundation, a quarter of the world’s adults have metabolic syndrome and people with metabolic syndrome are twice as likely to die from, and three times as likely to have, a heart attack or stroke compared with people without the syndrome.

 

New Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study

 

A new SPARCL analysis was conducted to evaluate if treatment with Lipitor 80 mg was associated with significant protection from coronary events after a recurrent stroke or mini-stroke. In more than 850 patients who suffered a recurrent stroke or mini-stroke during the trial:

 

Lipitor 80 mg reduced patients’ risk of experiencing major coronary events (death from cardiac causes, heart attack, or resuscitation after cardiac arrest) by 53 percent compared with placebo.

The benefits of Lipitor 80 mg in patients with a recurrent stroke or mini-stroke seen in this analysis are consistent with the primary SPARCL results which demonstrated the benefit of Lipitor 80 mg in reducing stroke and coronary events among all patients in the study (n=4,731).

 

About Stroke

 

Stroke is the third leading cause of death and the leading cause of adult disability in the United States and industrialized European nations. About 700,000 Americans and 1.1 million Europeans suffer from a stroke or mini-stroke annually.

 

According to a recent article in the journal Neurology, many patients hospitalized with stroke or mini-stroke, including those with known high cholesterol and those taking lipid lowering agents, have an LDL level that is higher than recommended in national treatment guidelines. Stroke patients with coronary heart disease are at the greatest risk of cardiovascular events yet are the least likely to be at guideline-recommended LDL levels. The authors suggest that future guidelines for lipid management may require additional revision to reflect the results of newer trials such as SPARCL that support the use of statins in stroke patients without coronary heart disease.

 

About the Overall CARDS Study

 

The CARDS study, published in The Lancet in 2004, evaluated patients (n=2,838) with type 2 diabetes who did not have existing cardiovascular disease, but had one or more risk factors for it. Lipitor 10 mg significantly reduced the risk of major cardiovascular events by 37 percent and the risk of stroke by 48 percent compared with placebo.

 

In CARDS, Lipitor was well-tolerated. The overall frequency of adverse events or serious adverse events did not differ between Lipitor and placebo.

 

About the Overall SPARCL Study

 

The SPARCL study, published in the New England Journal of Medicine in 2006, is the only study to date evaluating the benefits of a statin solely in patients with a prior stroke or mini-stroke (n=4,731). Lipitor 80 mg reduced the risk of an additional stroke by 16 percent and major coronary events by 35 percent compared with placebo. In a post-hoc analysis of the SPARCL trial, there was a higher incidence of hemorrhagic stroke in patients taking Lipitor 80 mg compared with patients taking placebo. Patients with prior hemorrhagic stroke at study entry appeared to be at an increased risk of hemorrhagic stroke.

 

In SPARCL, Lipitor was well-tolerated. The rate of side effects such as elevated liver enzymes, muscle weakness or rhabdomyolysis were low and consistent with the known safety profile.

 

About Lipitor

 

Lipitor is the most extensively studied and most prescribed cholesterol-lowering therapy in the world, with nearly 133 million patient-years of experience. Lipitor is supported by an extensive clinical trial program involving more than 400 ongoing and completed trials with more than 80,000 patients.

 

Important US Prescribing Information

 

Lipitor is a prescription medication. It is used in patients with multiple risk factors for heart disease such as family history, high blood pressure, age, low HDL (“good” cholesterol) or smoking to reduce the risk of a heart attack, stroke, certain types of heart surgery and chest pain.

 

Lipitor is also used in patients with type 2 diabetes and at least one other risk factor for heart disease such as high blood pressure, smoking or complications of diabetes, including eye disease and protein in urine, to reduce the risk of heart attack and stroke.

 

Lipitor is used in patients with existing coronary heart disease to reduce the risk of heart attack, stroke, certain kinds of heart surgery, hospitalization for heart failure, and chest pain.

 

When diet and exercise alone are not enough, Lipitor is used along with a low-fat diet and exercise to lower cholesterol.

 

Lipitor is not for everyone. It is not for those with liver problems. And it is not for women who are nursing, pregnant or may become pregnant.

 

Patients taking Lipitor should tell their doctors if they feel any new muscle pain or weakness. This could be a sign of rare but serious muscle side effects. Patients should tell their doctors about all medications they take. This may help avoid serious drug interactions. Doctors should do blood tests to check liver function before and during treatment and may adjust the dose. The most common side effects are gas, constipation, stomach pain and heartburn. They tend to be mild and often go away.

 

For additional product information, visit www.Lipitor.com.

 

Contacts

Pfizer

Vanessa Aristide, 212-733-3784

Rebecca Hamm, 212-733-8811

Onsite: 917-599-7752

 

Source: Pfizer Press Release

Analysis of International Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in Patients With Advanced Lung Cancer