New Covalent Drug Treats Hepatitis C

New Covalent Drug Treats Hepatitis C
Drug Discovery & Development - November 29, 2010

Avila Therapeutics, Inc., a biotechnology company developing novel targeted covalent drugs, has published research in Nature Chemical Biology demonstrating the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug. In the paper titled "Selective Irreversible Inhibition of a Protease by Targeting a Non-Catalytic Cysteine", Avila used its proprietary Avilomics™ platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.
Importantly, the published research demonstrates that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases. This is the first report of the irreversible covalent approach being successfully extended to proteases, a very broad class of proteins that includes many important potential drug targets.
"This research elevates covalent drug design to a fundamentally new level," said Simon Campbell, PhD, CBE, FMedSci, FRS, a renowned scientist and former Senior Vice President for Worldwide Drug Discovery and Medicinal R&D Europe of Pfizer. "By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets."
"This publication showcases the creation of a whole new class of small molecule drugs," said Juswinder Singh, PhD, Chief Scientific Officer of Avila and a co-author of the paper. "This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease."
In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:

• A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM .
• Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
• Very high selectivity of the Avila compounds was demonstrated by showing no notable inhibition of a panel of human proteases in biochemical assays with additional specificity demonstrated in cellular assays; this was contrasted experimentally with Telaprevir, an HCV protease inhibitor in late-stage clinical testing which demonstrated off-target biochemical activity against several human targets.

Avila has subsequently optimized additional drug candidates, yielding current development candidates, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild- type HCV protease as well as multiple genotypes and mutant forms of HCV protease.
Date: November 28, 2010
Source: Nature Chemical Biology

AMR101 Treats Very high Triglycerides

AMR101 Treats Very high Triglycerides
Drug Discovery & Development - November 29, 2010

Amarin Corporation plc, a clinical-stage biopharmaceutical company with a focus on cardiovascular disease, reported positive, statistically significant top-line results from the MARINE study, its first Phase 3 clinical trial of lead drug candidate AMR101. The MARINE study, investigating AMR101 as a treatment for very high triglycerides (≥500 mg/dL), met its primary efficacy endpoints as defined in the clinical trial protocol and demonstrated a positive safety profile.  The company believes that AMR101 has the potential to be the best-in-class product for this indication and that the MARINE study results may support additional patentable claims that could further protect the company's rights to this product through 2030.
The study's primary endpoint, the percent change in triglyceride (TG) levels from baseline to week 12, was met for both the 4 gram and 2 gram dose groups. The MARINE study was required to meet a stringent level of statistical significance of 1% (p < 0.01), as agreed in the company's SPA (Special Protocol Assessment) with the FDA. Twenty-five percent of patients were on background statin therapy. The patient group treated with 4 grams of AMR101 showed a significant median TG decrease of 33 % (P < 0.0001) compared to placebo, and the patient group treated with 2 grams of AMR101 showed a significant median TG decrease of 20 % (P = 0.0051) compared to placebo. The median baseline triglyceride levels were 703 mg/dL, 680 mg/dL and 657 mg/dL for the patient groups treated with placebo, 4 grams of AMR101 and 2 grams of AMR101, respectively.
In a pre-specified secondary analysis in the subgroup of patients with baseline TG > 750 mg/dL, representing 39% of all patients, the effect of AMR101 in reducing TG levels was even more pronounced. In this group, the median decrease in TG levels from placebo was 45% for 4 grams and 33% for 2 grams, both statistically significant (P= 0.0001 for 4 grams and P= 0.0016 for 2 grams, respectively). The median baseline TG levels in this subgroup were 1052 mg/dL, 902 mg/dL and 948 mg/dL for placebo, 4 gram and 2 gram groups, respectively.  In addition, the subgroup of patients on background statin therapy had much greater median reductions in TG, which were also statistically significant, than those not on statin therapy.
Importantly, AMR101 did not result in an increase in median LDL-C compared to placebo at either dose (-2.3% for the 4 gram group and +5.2% for the 2 gram group [p=NS]). This is the first and only triglyceride-lowering therapy studied in this population with very high triglyceride levels to show a lack of elevation in LDL-C. Furthermore, there was a statistically significant decrease in median non-HDL-C (total cholesterol less "good cholesterol") compared to placebo with both of the AMR101 treated groups (-18% for the 4 gram group [p < 0.001] and -8% for the 2 gram group [p < 0.05]).
There were also statistically significant reductions in several important lipid markers, including Apo B, Lp-PLA2 (Lipoprotein-phospholipase A2), VLDL-C and Total Cholesterol. These results are particularly encouraging given that no other TG-lowering therapy studies have shown such results. For these achieved endpoints, p-values were <0.01 for most and <0.05 for all.  Apo B (Apolipoprotein B) is a sensitive index of residual cardiovascular risk and is generally considered to be a better predictor than LDL-C.  Lp-PLA2 is an enzyme found in blood and atherosclerotic plaque; high levels have been implicated in the development and progression of atherosclerosis. Furthermore, AMR101 appeared to be very well tolerated with a safety profile that appears to be both comparable to placebo and more favorable compared to other triglyceride lowering therapies. There were no treatment-related serious adverse events in the MARINE study.  The company will present more details of these results at an upcoming scientific meeting.
Commenting on the results of the study, Harold Bays, M.D., Medical Director, Louisville Metabolic and Atherosclerosis Research Center, and Principal Investigator of the study, stated, "The MARINE trial included a study population of patients with very high TG levels (i.e. > 500 mg/dl).  In this study, AMR101 reduced TG levels to within the range observed with common approved triglyceride-lowering drugs.  Clinicians are aware, and some may have concerns, that common TG-lowering agents may raise LDL-C by 40 – 50% in patients with very high TG levels.  In the MARINE trial, AMR101 did not significantly increase LDL-C levels.  Another surprise to me was the degree of TG-lowering efficacy in the statin-treated group, which exceeded the TG lowering in the non-statin treated group.  It was also reassuring that the safety and tolerability of AMR101 was similar to placebo.  Adding these favorable findings to the significant reductions in total cholesterol, non-HDL-C, Apo B, and Lp-PLA2 levels, this suggests that AMR101 may prove to represent an effective, and safe alternative treatment option to improve cardiovascular risk factors in patients with very high triglycerides.  In summary, the results of the MARINE trial suggest that AMR101 may prove to represent a "first in class" EPA TG-lowering agent that not only represents a new chemical entity, but a potential novel therapy with favorable lipid efficacy effects that differ from common TG-lowering agents, such as fibrates and previously approved prescription omega-3 drugs. We very much look forward to presenting the full dataset at a scientific meeting."
Joseph S. Zakrzewski, Executive Chairman and Chief Executive Officer of Amarin, added, "The MARINE study was conducted in a population representative of millions of people with very high triglyceride levels, including more than 3.8 million in the U.S. alone. We believe that these results and the overall profile of AMR101 position the drug candidate to be best in class in this market. Furthermore, the MARINE study results are encouraging, especially the positive outcomes with respect to LDL-C and other lipids, as we await the results of the ongoing ANCHOR study. This separate Phase 3 study is designed to investigate AMR101 in patients with high triglycerides (≥200 and <500mg/dL) with mixed dyslipidemia treated with statins, a patient population for which no drug in this class is currently approved. While the market for a drug labeled for treatment of triglycerides of ≥500 mg/dL is already proven to be a billion dollar market, there are ten times the number of patients with triglycerides of ≥200 and <500 mg/dL."
Based on the timing and nature of these results, Amarin intends in 2011 to submit a New Drug Application (NDA) seeking approval to market and sell AMR101 in the U.S.  Previous company guidance projected 2012 for the NDA submission.  The company further added that, based on the positive results of the MARINE trial, Amarin has advanced additional patent claims to add to its growing portfolio of U.S. and international intellectual property claims related to AMR101.
Date: November 29, 2010
Source: Amarin Corporation plc 

Antiplatelet Mix Raises Risk of Bleeding
Drug Discovery & Development - November 23, 2010

Dual antiplatelet therapy—treatment with the medications clopidogrel and aspirin together to prevent blood clots—poses a clinically significant risk of hemorrhage that should be considered before prescribing, according to a report in the November 22 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
Dual antiplatelet therapy with clopidogrel plus aspirin is commonly used to prevent blood clots in patients with cardiovascular disease, according to background information in the article. The treatment has demonstrated a benefit in reducing the formation of clots in stents and also in preventing blocked blood vessels in patients who have had a heart attack or other form of acute coronary syndrome. Although warfarin remains the standard of care for treatment of a wide variety of clot-related conditions, the strategy of dual antiplatelet therapy has gained increased attention as an alternative for some patients.
Nadine Shehab, Pharm.D., M.P.H., of the Centers for Disease Control and Prevention, Atlanta, and colleagues used national databases to identify emergency department visits for hemorrhage-related adverse events from either dual antiplatelet therapy or warfarin between 2006 and 2008.
The researchers identified 384 annual emergency department visits for hemorrhage-related adverse events among patients taking dual antiplatelet therapy and 2,926 annual visits for those taking warfarin. Approximately 60 percent of emergency department visits for dual antiplatelet therapy consisted of epistaxis (nosebleeds) or minor hemorrhages. The estimated rate of emergency department visits was 1.2 per 1,000 outpatient prescription visits among patients taking dual antiplatelet therapy compared with 2.5 per 1,000 outpatient prescription visits taking warfarin.
"Although we found the overall risk of hemorrhage-related emergency department visits to be three-fold higher for warfarin than for clopidogrel plus aspirin, a little more than one-half of the emergency department visits for acute hemorrhages due to warfarin were composed of minor hemorrhages and one-quarter of warfarin-related emergency department visits, overall, were for elevation of laboratory coagulation variables without documentation of hemorrhage," the authors write. When only documented hemorrhages were considered, the risk of an emergency department visit was only doubled (rather than tripled) among warfarin users compared with those taking clopidogrel plus aspirin.
"The beneficial role of dual antiplatelet therapy is well established in patients with acute coronary syndromes and may potentially expand to a subset of patients with atrial fibrillation," the authors conclude. "Ultimately, for each patient, the hemorrhagic risk associated with dual antiplatelet therapy will be determined by his or her specific demographic and clinical risk factors, underlying diagnosis, treatment setting and quality of clinical care. Broadly, however, these nationally representative findings on adverse events indicate that the hemorrhagic risk of clopidogrel plus aspirin therapy is substantial and suggest a need to approach that risk with vigilance."
Date: November 22, 2010
Source: JAMA and Archives Journals

Positive Results in Scar-Reducing Drug Trial

Positive Results in Scar-Reducing Drug Trial
Drug Discovery & Development - November 23, 2010

Renovo Group plc announced positive results in a clinical trial designed to establish the safety and efficacy of a new formulation of the scar revision drug Juvista intended for use in children. The study of Juvista Paediatri included 84 patients and the statistical analysis (p<0.0001) indicated a profound result much more than the hurdle rate of 21% improvement set in the phase 3 trial.
Highlights of the announcement include:
• 84 healthy male and female subjects participated in a double blind, placebo controlled, within subject comparative study of the safety and efficacy of Juvista and Juvista Paediatric on scar appearance after 12 months using the Global Scar Comparison Scale (the primary endpoint agreed with the EMA for Renovo’s ongoing EU Phase 3 trial).
• Single doses of Juvista Paediatric administered immediately after wound closure (500 and 1000 ng/100μl/linear cm of wound margin) significantly improved the appearance of surgical 1cm incision scars compared to placebo (p<0.0001) when assessed by an expert panel using the Global Scar Comparison Scale at 12 months.
• Statistically significant improvements were also observed for single doses of Juvista Paediatric (500 and 1000 ng/100μl/linear cm of wound margin) for the investigator’s assessment directly on the patient at 12 months using the Global Scar Comparison Scale (p<0.001, p<0.0001 respectively).
• The current top dose of Juvista in the ongoing adult EU Phase 3 efficacy study (500 ng/100μl/linear cm of wound margin administered twice) was re-confirmed as the optimal dose for improvement of scar appearance (p<0.0001) as no further efficacy (in fact a slight decrease) was achieved after dosing 1000ng /100μl/linear cm of wound margin, either once or twice.
Date: November 23, 2010
Source: Renovo Group plc 

Vertex Submits Telaprevir NDA

Vertex Submits Telaprevir NDA
Drug Discovery & Development - November 23, 2010

Vertex Pharmaceuticals Incorporated announced that it has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for telaprevir, Vertex's investigational treatment for people with hepatitis C. The NDA submission is supported by results from three Phase 3 studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in people chronically infected with genotype 1 hepatitis C virus (HCV) who were new to treatment as well as those who were treated before but did not achieve a sustained viral response (SVR, or viral cure). The submission includes a request for Priority Review, which would reduce the FDA's review time from 10 months to six months. The FDA grants Priority Review status for several reasons, including if the medicine is considered a major advance in treatment.

"This submission is a milestone in our more than 15-year effort to change the way hepatitis C is treated," said Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex. "We are committed to working closely with the FDA to make telaprevir available as quickly as possible to the millions of people with hepatitis C who need new medicines to increase their chances for a viral cure."

All Phase 3 studies met their primary endpoints and results below are from the treatment arms where telaprevir was started immediately in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment.

In people with hepatitis C who were new to treatment (treatment-naïve):
• Up to 75% achieved a viral cure with telaprevir-based combination therapy, compared to 44% of people who received pegylated-interferon and ribavirin alone;
• A majority (58% in ADVANCE and 65% in ILLUMINATE) were eligible to reduce their treatment time by half — from 48 weeks to 24 weeks; and
• Data showed there was no benefit to extending total treatment from 24 weeks to 48 weeks in people whose virus was undetectable at weeks 4 and 12 with telaprevir-based therapy.

In the three major subgroups of people with hepatitis C who had not achieved a viral cure with a prior course of treatment (treatment-experienced):
• 83% of prior relapsers, 59% of prior partial responders and 29% of prior null responders achieved a viral cure with telaprevir-based combination therapy compared to 24%, 15%, and 5% of people in these subgroups, respectively, who received pegylated-interferon and ribavirin alone. These results were achieved with a simultaneous start of all three drugs for the first 12 weeks followed by pegylated-interferon and ribavirin alone for an additional 36 weeks.

The safety and tolerability results of telaprevir-based combination therapy were consistent across the Phase 3 studies. The most common adverse events regardless of treatment arm were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia, with the majority being mild or moderate in severity.

Hepatitis C is a serious disease, typically without symptoms, which affects up to 3.9 million people in the United States. Hepatitis C can lead to scarring of the liver (cirrhosis), resulting in liver failure, liver cancer and the need for liver transplantation. Approved medicines for people with genotype 1 hepatitis C are given for a year, and less than half of people treated with these therapies achieve a viral cure.4,5,6 Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir in Phase 2 and Phase 3 studies.

"In our trials, starting patients with 12 weeks of telaprevir-based combination therapy significantly improved viral cure rates compared to treatment with currently approved medicines, even in groups of people considered the most difficult to treat," said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. "We're also encouraged by telaprevir data that showed most patients new to therapy were able to achieve high viral cure rates and reduce their total treatment time by half."

Vertex is developing telaprevir in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America and Tibotec has rights in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

Vertex was granted Fast Track designation by the FDA for telaprevir in 2005. In mid-2010, as part of the Fast Track designation, Vertex began to submit completed sections of the NDA for review by the FDA on a rolling basis rather than wait until every section of the application was complete.
Date: November 23, 2010
Source: Vertex Pharmaceuticals 

Randomization and Trial Supply Management

Randomization and Trial Supply Management
Drug Discovery & Development - June 14, 2010

Medidata Solutions, a leading global provider of SaaS-based clinical development solutions, introduced Medidata Balance, a new randomization and trial supply management (RTSM) solution for clinical research sponsors and sites. Balance’s web-based technology, unified with the Medidata Rave  electronic data capture (EDC) and clinical data management (CDM) platform, and its simplified approach to dynamic randomization enable study teams to greatly reduce trial planning and implementation time, effort and costs and potentially reduce the number of subjects required to be enrolled.
An extremely critical part of the planning and execution of many trials—the design, implementation and conduct of a randomization plan to allocate patients to different treatment arms—can be a very complicated and time-consuming process. Randomization planning typically involves specification with spreadsheets, various computational methods and much iteration among functional groups, followed by a complex and lengthy software development project for the use of a telephone-based interactive voice-prompted response system (IVRS)—which often takes months to develop and test. The IVRS is used by clinical sites to enroll patients and allocate treatments, in addition to a separate EDC system used to collect often redundant patient data as well as clinical results. Attempts at reducing this redundancy by integrating the IVRS and EDC systems add complexity and time to the project, especially when the systems are provided by different vendors.
Medidata Balance offers life sciences companies a much higher level of efficiency and effectiveness in trial design and operation, eliminating the need for programming, separate tools or spreadsheets. Balance brings all elements of the design and execution of randomization and supply logistics into one web-based solution:
• A straightforward browser interface guides the creation of the randomization design;
• A powerful dynamic allocation algorithm creates the assignments to arms and strata;
• An integrated simulation tool tests the assignments and confirms the desired level of balance.
Once designed, all randomization and supply logistics information is immediately accessible by site staff via the Medidata Rave platform and browser interface in electronic case report forms (eCRF). As a result, enrolling subjects to different treatment arms, receiving treatment instructions and capturing and reporting clinical results during visits all take place in one, easy-to-use system.
“While IVRS and their newer web-based variants have played a key role in clinical research over the past several years, randomization and supply management offerings remain consistently service-heavy and custom-tailored,” said Glen de Vries, president of Medidata Solutions. “With Medidata Balance, we’re bringing to RTSM the same values that Medidata Rave brought to EDC—simple interfaces to configure complex behavior, short time-to-value, low total cost of ownership and truly scalable software-as-a-service (SaaS). These help our customers attack inefficiencies head-on and continue to evolve and improve the clinical trial process.”
Date: June 14, 2010
Source: Medidata Solutions 

BioClinica WebSend, a system that simplifies and accelerates image collection

Clinical Trial Management
Drug Discovery & Development - April 09, 2010

BioClinica, Inc., a global provider of clinical trial management services, has released BioClinica WebSend, a system that simplifies and accelerates image collection for clinical studies. WebSend transfers and tracks medical images in real-time, offering key benefits over the standard manual transport methods commonly used in imaging trials, including faster delivery of  image data,  enhanced data quality with fewer site queries, and reduced cost.
BioClinica WebSend is complemented by BioClinica WebView, the proven and established solution for managing the electronic sharing, blinding, tracking, archiving and analysis of medical images for clinical trials worldwide.  Originally developed over 10 years ago by CardioNow, a business acquired by BioClinica from Agfa HealthCare in August 2009, BioClinica WebSend and WebView have evolved into a best-in-class solution for delivering true electronic clinical trial image management. 
“BioClinica WebSend offers clients speed and flexibility that is simply not available with other image transport solutions.  It allows any investigator site or imaging center globally to send all medical images to BioClinica electronically in a secure, regulatory-compliant manner.  Along with BioClinica WebView, WebSend manages the collection and validation of those images,” said Mark L. Weinstein, CEO of BioClinica, Inc.

“BioClinica WebSend and BioClinica WebView are further examples of how BioClinica continues to develop innovative solutions to help our customers better manage their clinical studies and achieve the best possible results. We remain committed to driving the advancement of image management for clinical trials with a blend of new technologies and services,” said David Pitler, President of BioClinica’s Bioimaging Services Division.  “The launch of these enhanced products exemplifies that commitment.”
BioClinica, Inc.

Treatment Delays Costly in HIV

Treatment Delays Costly in HIV
Drug Discovery & Development - November 23, 2010

HIV infected patients whose treatment is delayed not only become sicker than those treated earlier, but also require tens of thousands of dollars more in care over the first several years of their treatment.
"We know that it's important clinically to get people into care early because they will stay healthier and do better over the long run," says Kelly Gebo, M.D., M.P.H., an associate professor of medicine in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine and the study's senior author. "But now we know it's also more costly to the health care system for potentially decades and a serious drain on our limited health care dollars."
Gebo says her team's findings highlight the importance of motivating people who are at risk to seek HIV testing and of reducing the time between the first positive HIV test and the first visit to an HIV clinic for care.
Patients with HIV are living longer and healthier lives, thanks to advances in antiretroviral therapy, but those successes may erode when some wait too long into the course of their disease to get treatment — whether because they don't know they are infected with HIV, aren't sure how to access the health care system or have competing needs like mental health or substance abuse issues.
Dr. Gebo and her team's research, published in the December issue of the journal Medical Care, reviewed medical records of 8,348 patients at nine HIV clinics across the United States between 2000 and 2007. They found that more than 43 percent of patients were considered late entrants into the health care system, presenting at a clinic with extremely weakened immune systems, characterized by having CD4 counts below 200. CD4 cells are keys to a healthy immune system — healthy people have counts between 800 and 1,000. When CD4 cells are damaged, as they are by HIV, counts can fall dramatically, making patients more susceptible to infection and certain types of cancer.
Low CD4 counts "make it more likely that patients are going to have complications and more likely that their CD4 counts won't ever recover to normal levels even with antiretroviral treatment," Gebo says. Previous studies have shown that those who come to care late in the course of their disease have shorter survival and benefit less from antiretroviral therapy.
Gebo and her colleagues found that the average difference in cumulative treatment expenditures between early and late presenters ranged from $27,275 to $61,615 higher over the course of the first seven to eight years of treatment. Costs are higher for the late presenters because they tend to be sicker than early presenters, particularly the first year of treatment — and the cost gap doesn't shrink over time, she says. Late presenters are hospitalized more often, need to be put on costly antiretroviral therapy and antibiotics, and often must be treated for other diseases that have been exacerbated by a weakened immune system.
Date: November 22, 2010
Source: Johns Hopkins Medical Institutions 

Half of Depression Suffers Stop Meds

Half of Depression Suffers Stop Meds
Drug Discovery & Development - November 23, 2010

Most patients who take anti-depressants give up their treatment in less than six months, the minimum period recommended for treating severe depression and other derived pathologies. This is the conclusion of a new study carried out by Catalan researchers, which reveals that only 25% continue their treatment for more than 11 months.
"Only one in every five patients properly completes their treatment", Catalina Serna, co-author of the study, and an expert at the Jordi Gol Primary Care Research Institute (IDIAP) in Lleida, tells SINC.
From 2003 to 2007, researchers from the Catalan Institute of Health (ICS) and the IDIAP Jordi Gol analysed 7,525 patients who were starting anti-depression treatment, looking at how long they continued with this treatment and the reasons why they gave it up.
The results, published this year in the journal European Psychiatry, pointed out that, of the 3.2% of the population who started treatment for depression, 56% stopped taking their medication during the first four months, and less than 25% of the cohort continued their treatment for more than 11 months.
The researchers say patients are most likely to give up their medication during the acute stage of depression (the first months). "The levels to which they stick to their treatment also declines steeply between the first four and 12 months of the monitoring period", Serna points out.
"In our study, only 22% of patients completed their treatment", the expert explains. "The higher completion rates seen in chronic cases are in multiply-medicated patients, who are twice as likely as other patients to continue with their treatment for depression (31% vs. 15.3%).
Men are more likely to give up treatment
Meanwhile, men are more at risk of giving up their treatment earlier than women (50% of men gave up their medication after two months, while 50% of women gave it up after three months).
Depression is one of the commonest psychiatric diseases among adults, above all in industrialised countries. A European study carried out in 2004 found that almost 13% of individuals surveyed reported having a serious depressive illness at some point in their lives. This study revealed that in Spain, where anti-depressant use has risen in line with the availability of new drugs, 10.5% of the population suffers from depression.
Date: November 22, 2010
Source: Spanish Foundation for Science and Technology 

Statins May Improve Liver Function

Statins May Improve Liver Function
Drug Discovery & Development - November 24, 2010

Contrary to widespread belief, patients with abnormal liver function who are given long-term statin treatment do not face an increased risk of liver disease, according to an Article published Online First in The Lancet. In fact, statins can improve liver function in patients with abnormal liver tests. Moreover, this study is the first to show a substantially greater cardiovascular benefit in patients with abnormal liver function tests compared with patients who have normal liver tests. These findings suggest that statins are a safe and promising treatment strategy for patients with non-alcoholic fatty liver disease (NAFLD).
Statins inhibit the liver's production of cholesterol and long-term treatment reduces the risk of cardiovascular events such as heart attacks and strokes. A rare adverse effect of statin use is increased levels of liver enzymes or serum transaminases like alanine aminotransferase (ALT). As a result, many physicians are reluctant to prescribe statins to patients with elevated ALT.
Most patients with high ALT will have NAFLD which affects up to a third of American, European and Japanese adults. The disease is common in patients with high cholesterol who have a substantially increased risk of cardiovascular disease and who would benefit from treatment with statins. However, the safety and efficacy of long-term statin treatment in these patients is unclear. Previous small and short-term studies in patients with raised ALT because of NAFLD have suggested that they are safe and improve liver tests and liver histology.
To provide more evidence, a team led by Vasilis Athyros from the Hippokration University Hospital in Thessaloniki, Greece and Dimitri Mikhailidis from University College London, London, UK, conducted a post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study* to assess whether long-term (3 year) statin treatment (mainly atorvastatin) is safe and effective in patients thought to have NAFLD. Of 437 patients with moderately abnormal liver tests (defined as less than three times the upper limit of normal before beginning treatment), 227 were treated with a statin and 210 were not treated.
Overall, liver-related adverse effects occurred no more often in the group who were given statins. Over 3 years follow-up, ALT improved or normalised in patients who were given statins, but in the group not taking statins liver tests worsened.
Importantly, patients who started the trial with abnormal liver function tests gained the greatest cardiovascular benefit of all—showing a 39% lower risk of having a cardiovascular event than patients in the GREACE study who had treated with a statin who had normal liver tests, and a 68% reduction in the relative risk of cardiovascular events compared with patientsfrom GREACE who did not receive a statin.
The authors conclude: "The risk-to-benefit ratio of long-term statin treatment favours statin administration even for patients with moderately abnormal liver tests."
In an accompanying Comment, Ted Bader from the University of Oklahoma Health Sciences Center, Oklahoma City, USA, says that: "For too long, a raised ALT after starting a statin has been erroneously thought to represent liver disease. For too long, patients with liver disease have been denied statins for their hypercholesterolaemia."
He points out that: "Despite the absence of liver injury from statins, a US survey showed that 50% of academic physicians would be reluctant to give a statin to a patient with an ALT of more than 1.5 times the upper limit of normal…100% of patients who need statins…would therefore be denied a statin."
He concludes: "Most physicians believe that statins cause liver disease because of the language of package inserts. Drug companies should be encouraged to request the deletion of this point from the insert."
Date: November 23, 2010
Source: Lancet 

Painkiller May Be Leading to Suicides

Painkiller May Be Leading to Suicides
Drug Discovery & Development - November 24, 2010

The active agent ziconotide, the synthetic toxin of the cone snail (Conus magus), was acclaimed a safe alternative to morphine when it was introduced six years ago. Now it is increasingly suspected of causing patients to commit suicide. Researchers working under the auspices of Prof. Christoph Maier (Director of the Pain Clinic Bergmannsheil at the Ruhr University in Bochum) presume that ziconotide not only suppresses the transmission of pain stimuli, but also deteriorates the frame of mind and could simultaneously reduce anxiety and impulse control. These mechanisms could promote suicidal tendencies in vulnerable patients. The research scientists thus advise careful diagnosis and monitoring of the psychic condition of patients treated with ziconotide. They have published their findings in the Medical Journal Pain.
Alternative to opioids for severe painZiconotide has numerous advantages, including the fact that it does not have any of the side effects typically associated with opioids, such as respiratory depression (asphyxia). Moreover, it does not lead to tolerance development. It has been on the European and American market since 2004, being administered to patients with intrathecal pumps if opioids do not suffice or if these trigger inacceptable side effects. Recently, the number of reports on the psychic side effects of ziconotide has increased. The researchers in Bochum analysed numerous studies, registering an increasing number of attempted suicides, which the original authors had not attributed to the ziconotide treatment. In PAIN, the physicians from RUB present two new cases, which underscore the suspicion that ziconotide enhances suicidal ideation.
Suicide despite pain relief and normal test resultsAs Prof. Maier stated, the first case is particularly tragic, the patient concerned, who had had pain is his feet for many years and undergone numerous unsuccessful treatments, having experienced a distinct improvement and pain relief for the first time when treated with ziconotide. There were no side effects. Tests disclosed that his depressiveness, which had also not been particularly marked before the ziconotide treatment commenced, even decreased. After a good three weeks, he appeared to be happy to all concerned. But two months after the ziconotide treatment had commenced he unexpectedly committed suicide. A further patient, a 39-year-old woman, who had undergone pain treatment for backache for 14 years, had had depressive phases 20 years previously and had attempted suicide after a pregnancy. Two months after the ziconotide treatment had commenced – which, according to current recommendations, should never have been administered to her in the first place due to her medical history – she mentioned that she had increased suicidal ideation. Moreover, she complained of other psychic side effects with hallucinations, confusion and partial amnesia, which had resulted in two severe car accidents. It is conceivable that the accidents were also of suicidal character. The physicians stopped the ziconotide treatment. Two weeks later both the suicidal ideation and the hallucinations were history.
Pharmaceutical companies and approval authorities must investigate the situationProf. Maier concludes that both cases underscore the assumption that there is a causality between ziconotide and suicidal tendencies. The pain specialist strongly emphasizes that the pharmaceutical companies and approval authorities should urgently investigate this yet again. All patients must be analysed for possible psychic disorders before treatment commences and closely monitored irrespective of pain relief due to the drug. The above-mentioned cases also underscore the fact that an increase in pain treatment when standard drugs fail is not always the correct mode of action. As Prof. Maier so aptly said, it is often even exactly the wrong path. This had already been pointed out a few weeks previously at the Congress of the German Pain Therapists (Kongress der deutschen Schmerztherapeuten)
Date: November 23, 2010
Source: Ruhr-University Bochum 

Positive New Data for Olesoxime

Positive New Data for Olesoxime
Drug Discovery & Development - November 24, 2010

Trophos SA a clinical stage pharmaceutical company developing innovative therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology, announced that Trophos and partners in the MS-Repair consortium delivered an oral presentation detailing Trophos’ novel approach in multiple sclerosis (MS) at the recent Society for Neuroscience (SfN) Meeting. The data presented demonstrate that olesoxime, Trophos’ lead compound, is a promising candidate for neuroaxonal repair and remyelination in white matter diseases, notably multiple sclerosis. The MS-Repair project is supported by the French Agence Nationale pour la Recherche (ANR).

“Disease progression in MS may reflect chronic and progressive neurodegeneration while relapses only reflect acute focal inflammation of the CNS. Hence, despite recent advances in treating relapses, therapeutic strategies promoting remyelination and providing neuroprotection are now the key needs in MS,” said Rebecca Pruss, CSO at Trophos. “We are very pleased to present with our academic partners this important work, which demonstrates the potential for olesoxime to bring a new treatment approach in multiple sclerosis through neuronal protection and remyelination aimed at addressing the long term progression and disability associated with the disease.”

The oral presentation of results was:
Novel compounds to promote axon repair and remyelination in multiple sclerosis, Bordet et al. It showed that Olesoxime dose-dependently promoted oligodendrocyte maturation and myelination in several in vitro (oligodendrocyte progenitor cells, oligodendrocyte – neuron co-cultures, organotypic brain slice cultures) and two in vivo models (cuprizone and lysophosphatidyl choline induced demyelination).

The results were obtained by a collaboration supported by the ANR project MS-Repair awarded to Trophos and two academic partners in Marseille, Dr Pascale Durbec at the Institut de Biologie du Développement de Marseille Luminy CNRS – Université de la Méditerranée UMR6216 and Dr Angèle Viola at the Centre de Résonance Magnétique Biologique et Médicale CNRS – Université de la Méditerranée UMR6612, in February 2009.

Olesoxime (TRO19622) is the lead compound of Trophos' proprietary cholesterol-oxime compound family of mitochondrial pore modulators, developed for their ability to promote the function and survival of neurons and other cell types under disease-relevant stress conditions through interactions with the mitochondrial permeability transition pore (mPTP). The data announced today show that olesoxime also has the ability to promote remyelination in addition to providing neuroprotection. Olesoxime is currently in two pivotal clinical efficacy studies, the first  in over 500 patients with Amyotrophic Lateral Sclerosis with results expected in the fourth quarter of next year (see releases of May 9 2009 and March 17 2010) and the second a recently started pivotal clinical study in Spinal Muscular Atrophy (see release of October 15 2010).
“These data on olesoxime in MS highlight the further strong potential of Trophos’ cholesterol oxime mitochondrial pore modulators in neurodegenerative diseases. Multiple sclerosis is one of the more common neurodegenerative diseases with an estimated 1.5 - 2.5 million sufferers globally,” added Damian Marron, CEO of Trophos. “We will continue this work to provide a complete package of data that will clearly demonstrate the value and therapeutic positioning of our compounds in multiple sclerosis.”
Date: November 23, 2010
Source: Trophos SA

FDA Approves Axiron for Testosterone Deficiency

FDA Approves Axiron for Testosterone Deficiency
Drug Discovery & Development - November 24, 2010

Eli Lilly and Company and Acrux announced that the U.S. Food and Drug Administration (FDA) has approved Axiron (testosterone) topical solution CIII for replacement therapy in men for certain conditions associated with a deficiency or absence of testosterone. Safety and efficacy of Axiron in males younger than 18 years of age have not been established.
Axiron is the first testosterone topical solution approved for application via an armpit (underarm) applicator. Other forms of testosterone replacement therapy include: oral tablets, buccal tablets, subcutaneous pellets, transdermal patches, injections and topical gels applied by the hands.
Although the total number of men with testosterone deficiency is unknown, it has been estimated that up to 13 million men over 45 years of age in the U.S. may have symptoms associated with low testosterone. Clinical trial data indicated that Axiron can restore blood concentration of testosterone within the normal range in most men.
"Lilly is proud to expand our focus in men's health," said David Ricks, president, Lilly USA. "The addition of Axiron to our product portfolio reinforces Lilly's commitment to provide innovative treatment options for patients."
"The FDA approval is a major milestone for Axiron and for Acrux," said Dr. Richard Treagus, chief executive officer, Acrux. "After years of research, we are excited to partner with Lilly to provide this novel application method for men with low testosterone."
Date: November 23, 2010
Source: Eli Lilly and Company 

Pre-exposure Prophylaxis Reduces HIV Risk

Pre-exposure Prophylaxis Reduces HIV Risk
Drug Discovery & Development - November 24, 2010

In a significant advance for HIV prevention research, a clinical trial confirms that the same drugs used for treating HIV can also help prevent HIV infection in the first place.
The study, known as iPrEx, is important because it gives credence to an HIV prevention approach called oral pre-exposure prophylaxis (PrEP), which involves the use of antiretrovirals (ARVs) by people who are HIV-negative and at high risk of infection. It is the first of five large-scale effectiveness trials testing oral PrEP to report results, which were published online in the New England Journal of Medicine today.
The results represent a major boost in efforts to combat HIV worldwide, say researchers from the Microbicide Trials Network (MTN), which is conducting VOICE, an ongoing study of both oral PrEP and a vaginal microbicide. Yet, as a trial involving one particular high-risk group – men who have sex with men – the iPrEx findings cannot be viewed as wholesale endorsement for the widespread use of PrEP at this time, they caution. Until other studies are completed, definitive conclusions cannot be made about how PrEP should or should not be used and in whom it would be safe and effective.
The iPrEx study showed that daily use of an ARV tablet called Truvada – together with comprehensive HIV prevention services and counseling – can help reduce the risk of HIV infection among men who have sex with men, who bear the burden of the epidemic in many parts of the world. Overall, there were nearly 44 percent fewer HIV infections among participants who were assigned to take Truvada every day than among those who took a placebo tablet.
"iPrEx has proved the concept of oral PrEP, and now it's up to the field to build on this success and work toward realizing the full potential of this promising approach in different at-risk populations, such as injection drug users and women in places like sub-Saharan Africa. None of us can do this alone. But collectively, I am convinced that we can, and that there will be the day when we have several safe and effective methods for preventing HIV," commented Sharon Hillier, Ph.D., professor and vice chair for faculty affairs, and director of reproductive infectious disease research in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, and principal investigator of the MTN.
The iPrEx study involved 2,499 participants from Peru, Ecuador, Brazil, the United States, South Africa and Thailand who were randomly assigned to one of two study groups: Truvada (a combination of tenofovir and emtricitabine) or placebo. All participants received safer sex counseling and free condoms, and were tested for HIV and other sexually transmitted infections (STIs) at each monthly visit throughout the time they were in the study. Of the 1,248 participants assigned to the placebo tablet group, 64 acquired HIV during the study, compared to 36 out of the 1,251 in the Truvada group.
iPrEx was conducted by an international team led by researchers from the Gladstone Institute of Virology and Immunology and affiliated with the University of California, San Francisco. It was funded by the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS), a component of the U.S. National Institutes of Health, with co-funding from the Bill & Melinda Gates Foundation. U.S.-based Gilead Sciences, Inc., donated the study product.
"The findings of this study have immense implications for the entire HIV prevention field, but most notably for global efforts focused on the population of men who have sex with men engaging in unprotected receptive anal intercourse. We clearly must find ways to prevent HIV infection via this route of transmission, whether through oral PrEP or with a rectal microbicide, or a combination of approaches, which must also include condoms. Condoms are still the most effective prevention method we have for preventing sexual transmission of HIV, both rectally and vaginally," noted MTN Co-Principal Investigator Ian McGowan, M.D., Ph.D., FRCP, professor of medicine in the division of gastroenterology, hepatology and nutrition with a joint appointment in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine.
Among those who took the drug more than 90 percent of the time, there were nearly 73 percent fewer HIV infections, according to pill and bottle counts and self-reports. There were 50 percent fewer HIV infections among participants who took the drug at least half of the time. In a subset of participants in the Truvada group, blood tests measuring levels of activated drug indicated that only half had taken the study drug as directed. However, in those participants whose blood levels suggested that they were compliant with pill taking, HIV risk was reduced by more than 90 percent compared to those who were not.
"This is a hugely significant finding that gives us great hope in the promise of ARV-based prevention if used as directed. It's now even more important that studies like VOICE provide the best information they can, so that we can know just how effective different ARV approaches are in diverse at-risk populations. To do this, we need to work especially hard to ensure that people who participate in the PrEP trials are using their study product as directed," stated Jeanne Marrazzo, M.D., M.P.H., VOICE Study co-chair, and professor of medicine in the division of allergy and infectious diseases at the University of Washington in Seattle. "No product or method will ever be effective if it's not used consistently."
VOICE – Vaginal and Oral Interventions to Control the Epidemic – is a Phase IIb trial designed to evaluate both the safety and effectiveness of oral PrEP, with either Truvada or tenofovir tablets, and also of a vaginal microbicide with tenofovir in gel form. It is the only trial evaluating both a tablet and a gel in the same study, which is important for measuring how each product works compared to its control (placebo gel or placebo tablet) and determining the approach women prefer. VOICE will involve approximately 5,000 women in Uganda, South Africa and Zimbabwe, who will use their assigned study product every day. The study began in September 2009. Results are expected in early 2013.
VOICE is MTN's flagship study and funded by NIAID/DAIDS, with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of the U.S. National Institutes of Health (NIH).
"We are very excited about the results of iPrEx, especially after the good news we received from the CAPRISA 004 study of tenofovir gel. We are now more hopeful than ever that in VOICE we will be able to confirm that ARVs taken daily, as either a tablet or a vaginal gel, are safe and effective for women, who desperately need ways they can protect themselves from HIV infection," added Mike Chirenje, M.D., FRCOG, associate professor and consultant gynecologist in the department of obstetrics and gynecology at the University of Zimbabwe in Harare and co-chair of the VOICE Study.
Indeed, the results of iPrEx come on the heels of CAPRISA 004 that in July of this year reported tenofovir gel reduced the risk of HIV by 39 percent among women in South Africa who used it before and after sex. The U.S. Food and Drug Administration has since indicated that it would consider approving tenofovir gel as an HIV prevention method for women depending on the results of VOICE.
Both Truvada and tenofovir (also known as Viread) are already approved drugs for the treatment of HIV when used in combination with other ARVs and are the only ARVs being tested as oral PrEP in HIV prevention trials. One of these trials, the Bangkok Tenofovir Study, involves 2,400 injection drug users in Thailand, whereas another study called FEM-PrEP is testing Truvada among 3,900 high-risk heterosexual women in Kenya, South Africa, Tanzania and Zimbabwe. Like VOICE, both ARVs are being evaluated in the Partners PrEP Study, a trial that involves 4,700 serodiscordant couples – in which one partner is HIV infected and the other is not – in Kenya and Uganda.
Date: November 23, 2010
Source: Microbicide Trials Network 

Abbott Releases Atrasentan Results

Abbott Releases Atrasentan Results
Drug Discovery & Development - November 22, 2010

Abbott announced positive results from a Phase 2 dose-ranging study of atrasentan, a highly selective endothelin A receptor antagonist in development to help slow chronic kidney disease (CKD) progression in patients with type 2 diabetic nephropathy (diabetic kidney disease). Study results suggest that atrasentan, used in conjunction with renin-angiotensin system (RAS) inhibitors, may reduce albuminuria (presence of protein in urine) for patients with type 2 diabetes. Albuminuria is the main sign of diabetic nephropathy and as kidney function decreases, the level of albumin in the urine rises. Results were presented at the annual American Society of Nephrology meeting in Denver, Colorado.
Key findings from the 8-week study of three doses of atrasentan (0.25 mg, n=22; 0.75 mg, n=22; 1.75 mg, n=22) vs. placebo were:
• Atrasentan significantly reduced urine albumin-to-creatinine ratio (UACR) in the 0.75 mg and 1.75 mg groups vs. placebo (P=0.001 and P=0.011 by repeated measures, respectively). The 0.25 mg dose had no significant effect
• Reduction from baseline to final UACR was 21%, 42%, and 34% in the 0.25 mg, 0.75 mg and 1.75 mg groups vs. 11% in placebo (P=0.292, P=0.023 and P=0.080, respectively)
• A statistically significant proportion of subjects achieved >40% reduction in UACR from baseline in the 0.75 mg group vs. placebo (50% vs. 17% respectively, P=0.029). The proportion of patients in the 0.25 mg and 1.75 mg groups (30% and 38% respectively) did not reach statistical significance.
• Peripheral edema (primarily mild) was the most common adverse event (14%, 18% and 46% for 0.25, 0.75 and 1.75 mg with p=0.007 for 1.75 mg vs. 9% in placebo)
"Several large clinical trials with RAS inhibitors have demonstrated that reductions in albuminuria are associated with a delay in the progression of diabetic nephropathy," said Donald E. Kohan, M.D., Ph.D., Professor of Medicine, Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah and lead investigator for the study. "These study results are encouraging and suggest that atrasentan may have an additional therapeutic role for albuminuria reduction on top of the current standard of care for patients with type 2 diabetes."
"The impact of chronic kidney disease is a growing global public health concern but few advancements in treatment have been made in the last decade that positively affect outcomes for patients with this progressive disease," said James Stolzenbach, Ph.D., divisional vice president, Dyslipidemia and Renal, Abbott. "Longer, outcome-driven clinical trials are needed to establish the safety and efficacy of atrasentan in diabetic nephropathy, but we are encouraged by the findings from this study and look forward to further evaluating atrasentan as a candidate for treating this type of chronic kidney disease."
Date: November 22, 2010
Source: Abbott 

Omthera Reaches Agreement With FDA

Omthera Reaches Agreement With FDA
Drug Discovery & Development - November 22, 2010

Omthera Pharmaceuticals, Inc., a privately-held emerging specialty pharmaceuticals company, today announced that it has reached an agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the design of its planned Phase 3 registration clinical trial of Epanova, the company’s lead compound for the treatment of patients with very high triglycerides. Epanova is an Omega 3 fatty acid containing a novel formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
The multi-center, placebo-controlled, randomized, double-blind, 12-week study will evaluate the efficacy and safety of three doses of Epanova in patients with fasting triglyceride (TG) levels of ≥500 mg/dL. The trial is expected to enroll approximately 300 patients and will be conducted in centers throughout North America, Europe and India. The primary endpoint of the trial, known as EVOLVE (EpanoVa fOr Lowering Very high triglyceridEs), is the percentage change in triglyceride level from baseline to week 12.
“An estimated five million people in the U.S., alone, have triglyceride levels greater than 500mg/dL, a serious lipid disorder that is rapidly growing in prevalence throughout the world,” said Jerry Wisler, President and Chief Executive Officer of Omthera. “This SPA marks an important milestone for Omthera, providing a clear regulatory pathway to approval for Epanova in this patient population.  We look forward to commencing this Phase III trial in the coming months.”
In addition to the EVOLVE study, Omthera has initiated a pharmacokinetic trial for Epanova, known as ECLIPSE (Epanova Compared to Lovaza In a Pharmacokinetic, Single-dose Evaluation), intended to demonstrate bioavailability advantages over currently available prescription Omega 3 products. Data from this study is expected in the first quarter of 2011.
“Cardiovascular disease continues to be the leading cause of death worldwide, and high triglycerides are an important contributing factor,” said John J. P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam and principal investigator for the EVOLVE study.  “Epanova therefore has the potential to be an innovative therapy to help patients control their triglyceride levels.”
Date: November 22, 2010
Source: Omthera Pharmaceuticals, Inc. 

Cancer Biomarker Completes Stage 1 Study

Cancer Biomarker Completes Stage 1 Study
Drug Discovery & Development - November 19, 2010

Stage 1 of HealthLinx Limited’s multi-centre, multi-site second study for OvPlex has returned excellent initial data for the two new biomarkers AGR2 and HTX010 being evaluated for accuracy in diagnosing ovarian cancer. To date, AGR2 and HTX010 data have been analysed in over 400 case and control samples.  Both AGR2 and HTX010 demonstrated statistically significant elevations in circulating plasma concentrations in both early stage (Stages I-II) and late stage (Stages III-IV) ovarian cancer patients.
These data are significant as they confirm and reinforce previous findings from several smaller pilot studies and now pave the way for HealthLinx to use these markers in its OvPlex multimarker panel. Previous modelling with these biomarkers demonstrated improved diagnostic efficiency of the OvPlex panel. In combination with the other OvPlex biomarkers we expect a marked improvement in the diagnostic efficiency in early (Stage I-II) ovarian cancer.
“Based upon our initial studies, we always believed that AGR2 and HTX010 would boost the performance of the OvPlex test. These early results are certainly in line with expectations and give us great confidence that our target of achieving a test with significantly enhanced diagnostic efficiency is feasible. Our aim is to fine tune the OvPlex test to ultimately provide sensitivity and specificity of at least 97% in the target patient population” said Nick Gatsios, Managing Director of HealthLinx.
Further development of the diagnostic use of AGR2 is of particular relevance as Healthlinx is the exclusive licensee of intellectual property covering the use of a highly specific monoclonal antibody that forms the basis of the blood test it has developed. HealthLinx has already signed a non-exclusive license deal for the use of one anti-AGR2 monoclonal antibody for research purposes to the Millipore Corporation, one of the world’s largest research reagent companies.
Based on these data, HealthLinx will now move forward with plans to further develop and partner the AGR2 immunoassay as a clinical diagnostic tool with a range of potential applications related to cancer diagnosis and monitoring.
“There are a range of potential applications emerging for the use of AGR2 as a cancer diagnostic. Although we are examining its potential diagnostic relevance in ovarian cancer patients, some characteristics of AGR2 expression suggest that it could be of value as a diagnostic/prognostic indicator in other cancer patients,” said HealthLinx chief scientific officer Dr Dominic Autelitano.
“It is very encouraging to see that the preliminary stage 1 data of the larger biomarker trial upholds and reinforces our initial ideas about AGR2 and HTX010. The next set of data analysis encompassing all of the original OvPlex multimarker panel is expected before the end of this quarter,” said Dr Autelitano.
Date: November 15, 2010
Source: HealthLinx Limited 

Neovacs Receives Authorization for Higher Dose

Neovacs Receives Authorization for Higher Dose
Drug Discovery & Development - November 19, 2010

Neovacs, a biotech company focused on an active immunotherapy technology platform (Kinoids) with applications in the treatment of autoimmune diseases, inflammatory diseases and cancer has received DSMB authorization to proceed to a higher dosage in its ongoing phase 1/2 trial in lupus.
Administration of the third dose level in patients recruited since September was completed as expected. Having reviewed the data related to these patients on November 5, the Data and Safety Monitoring Board, an independent committee which is responsible for overseeing the conduct of the study and in particular for patient safety, authorized Neovacs to proceed to the next higher and final dose of INF-α-Kinoid. Neovacs is now able to finalize recruitment of patients for this phase 1/2 trial, as planned.
The DSMB’s’ decision confirms the good tolerability of IFN-α-Kinoid to date, which has now been administered to patients at three dose levels. Rapid progress has been made so far in this Phase 1/2 trial and the company is confident in  achieving its objective of releasing preliminary results by the end of the first half 2011.
The study is placebo-controlled, double-blind with dose-escalation and randomization at each dose level. Patients must present symptoms of moderate disease and the primary objective of the ongoing study is to gather data on the tolerability and safety of IFN-α-Kinoid. Secondary objectives include analysis of the immune response and measurements of disease activity and IFN-α markers.
Date: November 15, 2010
Source: Neovacs 

Pain Drug May Hold Key to MS Treatment

Pain Drug May Hold Key to MS Treatment
Drug Discovery & Development - November 19, 2010

Successfully treating and reversing the effects of multiple sclerosis, or MS, may one day be possible using a drug originally developed to treat chronic pain, according to Distinguished Professor Linda Watkins of the University of Colorado at Boulder.
Watkins and her colleagues in CU-Boulder's department of psychology and neuroscience discovered that a single injection of a compound called ATL313 -- an anti-inflammatory drug being developed to treat chronic pain -- stopped the progression of MS-caused paralysis in rats for weeks at a time.
Lisa Loram, a senior research associate who spearheaded the project in Watkins' laboratory, presented the findings at the Society for Neuroscience's annual meeting held in San Diego this week.
MS is an inflammatory disease where the body's immune system attacks a protective sheath called myelin that encompasses nerves in the spinal cord and brain. As the disease progresses, the myelin develops lesions, or scars, that cause permanent neurological problems.
"What happens now with MS drugs is they slow or stop the progression of MS, but they don't treat it," Watkins said. "They don't take people back to normal because the lesions caused by MS don't heal."
Watkins, Loram and their colleagues hope to use spinal cord and brain-imaging technology to extend their studies to determine if lesions are being healed in rats that received an ATL313 injection.
"If we have a drug that is able to heal these lesions, this treatment could be a major breakthrough in how we treat the symptoms of MS in the future," she said.
The new findings were quite a surprise to Watkins. The team had originally wanted to look at the drug's potential in treating pain associated with MS, because about 70 to 80 percent of MS patients suffer from chronic pain that is not treatable.
"What we had originally thought about this class of compounds is that they would calm down glial cells in the spinal cord because their pro-inflammatory activation is what causes pain," she said.
Under normal circumstances glial cells are thought to be like housekeepers in the nervous system, Watkins said, essentially cleaning up debris and providing support for neurons. Recent work by Watkins and others has shown that glial cells in the central nervous system also act as key players in pain enhancement by exciting neurons that transmit pain signals.
"What's become evident is that glial cells have a Dr. Jekyll and Mr. Hyde personality," Watkins said. "Under normal circumstances they do all these really good things for the neurons, but when they shift into the Mr. Hyde formation they release a whole host of chemicals that cause problems like neuropathic pain and other chronic pain conditions."
They discovered that ATL313 appears to reset the glial cells from an angry activated state to a calm anti-inflammatory state that may heal MS lesions.
Date: November 18, 2010
Source: University of Colorado at Boulder 

FDA Approves Denosumab for Cancer Patients

FDA Approves Denosumab for Cancer Patients
Drug Discovery & Development - November 19, 2010

WASHINGTON (AP) - Biotech drugmaker Amgen says federal health regulators approved its bone-strengthening drug for preventing fractures and skeletal-problems in patients with advanced cancer.
The Food and Drug Administration cleared the company's drug denosumab for patients with solid tumors. The FDA approved the drug based on three studies that showed it worked at least as well as Novartis' Zometa in preventing bone-related complications.
Amgen already sells the drug under the name Prolia, but as a treatment for osteoporosis caused by menopause. The company will market the drug for its new use as Xgeva.
More than 50 percent of cancer patients experience complications when cancer spreads to their bones, according to the company.
Doctors will administer Xgeva to patients in once-a-month injections. The drug works by blocking a protein that breaks down bone cells.
Date: November 18, 2010
Source: Associated Press

Pfizer Slams Brakes on Apixaban Study

Pfizer Slams Brakes on Apixaban Study
Matthew Perrone
Drug Discovery & Development - November 19, 2010

Pfizer Inc. said it is halting a late-stage study of its highly anticipated blood thinner apixaban, due to dangerous bleeding among patients with a history of heart disease.
The drug, co-developed with Bristol-Myers Squibb Corp., has been touted as a potential blockbuster drug for its potential to prevent heart attacks and strokes without the bleeding side effects associated warfarin, a drug used since the 1950s.
But Pfizer said in a statement late it halted a 10,000-patient study of the drug because of "a clinically important increase in bleeding among patients."
The study was designed to find out whether adding apixaban to older blood-thinning medications would decrease rates of heart attack and related problems. The companies halted the study after a panel of medical experts said the drug's bleeding side effect outweighed its benefits on the heart
"We took our guidance from the data monitoring committee that has been monitoring this study, and their read out to us was that they saw an excess of bleeding with apixaban," said Dr. Jack Lawrence, head of apixaban development at Bristol-Myers Squibb.
All patients in the trial were already taking two other blood-thinning medications: Plavix and aspirin, the latter of which carries its own risks of bleeding.
"I think with any anti-thrombotic drug, bleeding is an unavoidable side effect. But in the successful therapies the efficacy benefit outweighs the bleeding risk," Lawrence said.
More than two years ago, the drugmakers reported that patients taking apixaban had significantly more bleeding than those taking aspirin.
Pfizer and Bristol-Myers are studying the drug in nine other trials for several uses, including: stroke prevention in patients with irregular heart rhythms and blood clot prevention in hip replacement patients.
Apixaban works by blocking a clotting protein called factor Xa, which is part of the clotting reaction. That is in contrast to drugs like Plavix, which work by preventing platelets from sticking together.
In October, the FDA approved the first drug in the factor Xa-blocking class - Pradaxa, made by the German firm Boehringer Ingelheim.
Pfizer is racing several other companies, including Johnson & Johnson, to bring the second drug in the class to the U.S. market.
Date: November 18, 2010
Source: Associated Press

Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients With Advanced Hepatocellular Carcinoma

Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients With Advanced Hepatocellular Carcinoma
A Randomized Trial
Ghassan K. Abou-Alfa, MD; Philip Johnson, MD; Jennifer J. Knox, MD; Marinela Capanu, PhD; Irina Davidenko, MD; Juan Lacava, MD; Thomas Leung, MD; Bolorsukh Gansukh, BS; Leonard B. Saltz, MD
JAMA. 2010;304(19):2154-2160. doi:10.1001/jama.2010.1672
Context  In a randomized phase 3 trial, 400 mg of sorafenib twice daily prolonged overall survival of patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A disease. In a phase 1 study, sorafenib combined with doxorubicin, 60 mg/m², was well tolerated by patients with refractory solid tumors. The combination of sorafenib and doxorubicin in patients with advanced HCC has not been evaluated in a phase 2 or 3 trial.
Author Affiliations: Department of Medicine (Drs Abou-Alfa and Saltz and Ms Gansukh) and Department of Epidemiology and Biostatistics (Dr Capanu), Memorial Sloan-Kettering Cancer Center, New York, New York; Cancer Research UK Institute for Cancer Studies, University of Birmingham, School of Cancer Sciences, Birmingham, England (Dr Johnson); Princess Margaret Hospital, Department of Medical Oncology, Toronto, Ontario, Canada (Dr Knox); Krasnodar City Oncology Center, Oncology Dispensary, Krasnodar, Russia (Dr Davidenko); Unidad Oncologica Del Neuquen, Oncology Service, Neuquen, Argentina (Dr Lacava); and Hong Kong Sanatorium and Hospital, Comprehensive Oncology Center, Hong Kong, China (Dr Leung).
Objective  To evaluate the efficacy and safety of doxorubicin plus sorafenib compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A disease.
Design, Setting, and Patients  In a double-blind phase 2 multinational study, conducted from April 2005 to October 2006, 96 patients (76% male; median age, 65 years [range, 38-82 years]) with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, Child-Pugh A status, and no prior systemic therapy were randomly assigned to receive 60 mg/m² of doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or placebo orally twice a day. The date of the last patient's follow-up was April 2008.
Main Outcome Measure  Time to progression as determined by independent review.
Results  Following complete accrual, an unplanned early analysis for efficacy was performed by the independent data monitoring committee, so the trial was halted. The 2 patients remaining in the placebo group at that time were offered sorafenib. Based on 51 progressions, 63 deaths, and 70 events for progression-free survival, median time to progression was 6.4 months in the sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median overall survival was 13.7 months (95% CI, 8.9-not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P = .006). Toxicity profiles were similar to those for the single agents.
Conclusions  Among patients with advanced HCC, treatment with sorafenib plus doxorubicin compared with doxorubicin monotherapy resulted in greater median time to progression, overall survival, and progression-free survival. The degree to which this improvement may represent synergism between sorafenib and doxorubicin remains to be defined. The combination of sorafenib and doxorubicin is not yet indicated for routine clinical use.
Trial Registration  clinicaltrials.gov Identifier: NCT00108953

Long-term effect of aspirin on colorectal cancer

The Lancet, Volume 376, Issue 9754, Pages 1741 - 1750, 20 November 2010

Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials

Original Text

Prof Peter M Rothwell FMedSci a , Michelle Wilson BSc a, Carl-Eric Elwin MD b, Prof Bo Norrving PhD c, Prof Ale Algra MD d, Prof Charles P Warlow FMedSci e, Prof Tom W Meade FRS f

Summary

Background

High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75—300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour.

Methods

We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data.

Results

In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60—0·96, p=0·02; mortality HR 0·65, 0·48—0·88, p=0·005), but not rectal cancer (0·90, 0·63—1·30, p=0·58; 0·80, 0·50—1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28—0·74, p=0·001; 0·34, 0·18—0·66, p=0·001), but not the distal colon (1·10, 0·73—1·64, p=0·66; 1·21, 0·66—2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20—0·63; 0·24, 0·11—0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36—0·92, p=0·02; 0·47, 0·26—0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61—2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75—300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70—6·05, p=0·15).

Interpretation

Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

Funding

None.

Navitoclax, a targeted high-affinity inhibitor of BCL-2,

The Lancet Oncology, Early Online Publication, 19 November 2010

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity

Original Text

Prof Wyndham H Wilson MD a , Prof Owen A O'Connor MD b, Prof Myron S Czuczman MD c, Ann S LaCasce MD d, John F Gerecitano MD e, Prof John P Leonard MD f, Anil Tulpule MD g, Kieron Dunleavy MD a, Hao Xiong PhD h, Yi-Lin Chiu PhD h, Yue Cui PhD h, Todd Busman MS h, Steven W Elmore PhD h, Saul H Rosenberg PhD h, Andrew P Krivoshik MD h, Sari H Enschede MD h, Rod A Humerickhouse MD h

Summary

Background

Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.

Methods

In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.

Findings

55 patients were enrolled (median age 59 years, IQR 51—67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40—218).

Interpretation

Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.

Funding

Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.