Gene Alteration Protects from Artery Disease

Gene Alteration Protects from Artery Disease
Drug Discovery & Development - January 28, 2011

A team of scientists at Johns Hopkins and elsewhere has discovered that a single alteration in the genetic code of about a fourth of African-Americans helps protect them from coronary artery disease, the leading cause of death in Americans of all races.
Researchers found that a single DNA variation - having at least one so-called guanine nucleotide in a base pair instead of a combination without any guanine - on a gene already linked to higher risk of coronary disease in other races is linked in blacks to decreased risk. Specifically, the study showed that otherwise healthy African-American men and women with the alternative genetic code had a fivefold reduction in the likelihood that their arteries would narrow or clog.
For African-Americans who inherited two copies of the guanine gene variant, one from each parent, the risk reduction was even more dramatic. They were 10 times less likely to have coronary heart disease, which disproportionately afflicts a greater number of African-Americans than whites or any other ethnic group. Nearly 17 million Americans have an arterial problem plaguing the heart, causing a half-million deaths, annually.
"What we think we have here is the first confirmed hereditary link to cardiovascular disease among African-Americans and it is a protective one," says senior study investigator and health epidemiologist Diane Becker, M.P.H., Sc.D. "This newly found link in African-Americans was not only protective instead of harmful but was also found at a precise location on gene CDKN2B, a gene close to the single base pair modification tied to other increased risk of coronary artery disease in other races."
Becker emphasizes that only an estimated quarter of blacks have the protective CDKN2B code, and only 6 percent have two copies, so "while a lot of African-Americans have this protective genetic modification, most do not." Advance testing for the genetic marker, she says, could ultimately in the future assist physicians in risk-stratifying those without inherited protection so they could be monitored more closely for early signs and symptoms of disease.
The findings are set to appear in the Journal of Human Genetics online Jan. 27.
Becker, a professor at both the Johns Hopkins University School of Medicine and Hopkins' Bloomberg School of Public Health, and a team that included researchers at Duke and Emory universities, also say their results, based on blood analysis from 548 black men and women in the Baltimore region and confirmed in several hundred more in the Atlanta and Durham, N.C., regions, help explain why earlier studies found potentially dangerous genetic connections to this type of heart disease in Caucasians, Hispanics and Asians, but failed to find a negative tie-in to the disease in blacks.
Earlier studies, says Becker, had involved genome-wide reviews in multiracial populations and taken "a needle in the haystack approach" to finding that one change in a string of some 58,000 base pairs, in a chromosomal region known as 9p21. That region, which includes CDKN2B, is associated with higher rates of coronary disease in non-blacks.
The team's latest analysis was successful, she believes, because it had a large and sufficiently broadly based black volunteer population. The study group comprised men and women between the ages of 26 and 60. Investigators also focused on the 9p21 region and a subsection of genetic material within called ANRIL that overlaps and is closely held to CDKN2B, but away from the deleterious genetic variant found earlier.
Johns Hopkins cardiologist Brian Kral, M.D., M.P.H., says the abundance of activity in this particular region of the genome, including CDK2NB and ANRIL, suggests that everyday replication of this zone could play a more fundamental, underlying role in the progression of coronary artery disease in all races.
Kral, an assistant professor at Johns Hopkins and its Heart and Vascular Institute. was co-lead investigator of the latest study, along with Hopkins genetic epidemiologist Rasika Mathias, Sc.D. The team next plans to further investigate the ANRIL subregion of 9p21 to see if any single genetic changes speed up or slow down progression of coronary diseases.
Blood samples for the genetic analysis came from a larger study being led by Becker of some 4,000 people from white and African-American ethnic backgrounds. Called the Genetic Study of Atherosclerosis Risk (GeneSTAR), under way at Johns Hopkins since 1983, it involves participants who were all healthy upon enrollment, with no existing symptoms of heart disease. All were monitored for at least five years with periodic check-ups to see who developed heart disease and who did not. Each had a sibling or a parent who had a history of coronary artery disease or some other symptom of blocked arteries, such as chest pain or shortness of breath. The latest study was based on results collected through 2007, by which time 35 black study participants had suffered some form of heart attack or needed an angioplasty or X-ray scan of the heart's blood vessels to confirm or rule out arterial blockages.
Date: January 28, 2011
Source: Johns Hopkins Medical Institutions 

Antibiotic Could Aid Cancer Fight

Antibiotic Could Aid Cancer Fight
Drug Discovery & Development - January 28, 2011

An antibiotic known for its immunosuppressive functions could also point the way to the development of new anti-cancer agents, researchers at the Indiana University School of Medicine have reported.
The study determined that the compound, tautomycetin, targets an enzyme called SHP2, which plays an important role in cell activities such as proliferation and differentiation. Interestingly, SHP2 mutations are also known to cause several types of leukemia and solid tumors. The findings were reported in the Jan. 28, 2011, issue of the journal Chemistry and Biology.
The potential for developing anti-cancer agents grew out of an attempt to determine how the compound, tautomycetin, exerts its immune suppression activities, said Zhong-Yin Zhang, Ph.D., Robert A. Harris Professor and chairman of the Department of Biochemistry and Molecular Biology.
The finding is also encouraging because SHP2 is a member of a large family of enzymes called protein tyrosine phosphotases (PTPs), which are important in the signaling processes that control all essential cellular functions. Dysregulation of PTP activity has been linked to several human diseases, including cancer, diabetes, and immune dysfunctions. But their makeup has made it difficult to find potential drugs to act on them, characteristics that have labeled the PTPs as “undruggable,” Dr. Zhang said.
“So we have identified a lead – a natural product produced by the bacteria Streptomyces – that should serve as a foundation for the development of therapeutic agents for a large family of protein tyrosine phosphotase targets. Until now these targets, including SHP2 for leukemia and other cancers, have been deemed undruggable,” he said.
Funding for the research was supplied by the National Institutes of Health.
Date: January 28, 2011
Source: Indiana University

FDA Approves Mylan Generics

FDA Approves Mylan Generics
Drug Discovery & Development - January 28, 2011

CANONSBURG, Pa. (AP) - Drugmaker Mylan Inc. said the Food and Drug Administration has approved four dose amounts of its generic version of Shionogi Pharma's Sular tablets for treating hypertension.
Mylan said the FDA approved 8.5-, 17-, 25.5- and 34-milligram doses of its Nisoldipine extended-release tablets. The company has been awarded six months of marketing exclusivity.
Date: January 28, 2011
Source: Associated Press

FDA Questions GSK on Avodart

FDA Questions GSK on Avodart
Drug Discovery & Development - January 28, 2011

BLOCK
GlaxoSmithKline Plc. said the Food and Drug Administration is asking the company for more information before approving the drug Avodart for men at risk of getting prostate cancer.
The company did not provide details on the FDA request.
In December, a panel of experts recommended that the FDA deny approval to Avodart for the new use, citing safety concerns. Panelists voiced concern that a small number of men taking drugs actually developed more aggressive tumors.
In its review at the panel meeting, the FDA presented figures showing that for every 60 men treated with Avodart for four years, one serious case of prostate cancer would be prevented. But for every 200 men treated during the same timeframe, one would develop a high-grade tumor.
At the time, the head of the FDA's office of oncology drug products said the drug should be held to a higher standard because it would be used in healthy men, unlike traditional cancer treatments.
Avodart is already approved and sold as a treatment for enlarged prostate.
Date: January 27, 2011
Source: Associated Press

Iniparib Fails Breast Cancer Trial

Iniparib Fails Breast Cancer Trial
Drug Discovery & Development - January 28, 2011

NEW YORK (AP) - French drugmaker Sanofi-Aventis SA said a clinical trial showed its drug candidate iniparib did not improve survival or slow disease progression in patients with breast cancer.
The late-stage clinical trial was designed to evaluate iniparib as a treatment for "triple negative" breast cancer, a type of breast cancer that is particularly difficult to treat. The study involved 519 patients whose cancer had metastasized or spread to other body parts. The trial compared a chemotherapy regimen including iniparib to one without it, evaluating its effects on overall patient survival and the amount of time patients lived before their disease resumed progressing or they died.
Sanofi-Aventis said there was not a significant difference between the regimen that included iniparib and the one that did not. Both regimens included the cancer drug Gemzar and the chemotherapy drug carboplatin.
However, the company said some patients who had been treated with one or two other therapies before enrolling in the trial did benefit from the iniparib regimen.
Sanofi-Aventis said 15 to 20 percent of breast cancer patients have the "triple negative" type of the disease, and they have a worse prognosis than other types of breast cancer. The disease is called triple negative because the tumors have normal levels of three proteins that are often found in high levels in breast cancer patients. Patients are usually treated with chemotherapy because the cancer does not respond to hormone-based drugs like tamoxifen, or drugs that target epidermal growth factors like Herceptin.
Date: January 28, 2011
Source: Associated Press

Regulatory Infrastructure Fosters Globalization of Drug Development

Regulatory Infrastructure Fosters Globalization of Drug Development
Doug Peddicord, PhD, Executive Director, Association of Clinical Research Organizations, Washington, DC
Drug Discovery & Development - February 16, 2010

Inexorably drug development is becoming—and in many ways, has already become—a global enterprise. Clinical research organizations (CROs) have not only benefited from this trend but have been major drivers behind globalization as the need for ever-larger and more complex clinical trials must be balanced with a desire for speed and efficiency. Accessing a global population of participants is a necessity to meet the demands of today’s drug development paradigm.
A July 2009 whitepaper commissioned by the Association of Clinical Research Organizations (ACRO) titled “The Case for Globalization: Ethical and Business Considerations for Clinical Research” found that globalized trials can reduce development time by half while lowering costs and maintaining quality and safety. For example, phase III cancer trials are conducted three times as fast if both U.S. and global sites are used, compared to U.S.-only sites.  What takes 5.8 years to enroll takes 1.9 years when a global trial is implemented.
Table 1: Number of Patients Enrolled per Active Trial Site: Established versus Emerging Markets¹

Established Markets	Patients per active site 2008	Change (in patients) since 2006
France	7.6	+1.3
Germany	8.3	+1.5
United Kingdom	8.1	+2.5
Canada	6.5	+0.3
United States	5.7	+0.4
Average Above Countries	7.2	+1.0

Emerging Markets	Patients per active site 2008	Change (in patients) since 2006
Eastern Europe	13.0	+2.6
Latin America	11.4	+2.3
Asia	11.1	+0.1
Average Above Regions	11.8	+1.7
Les Entreprises du Medicament (LEEM). (2008). The attractive position of France in International Clinical Research: 2008 survey assessed by Leem. Paris, France.

While CROs have performed the role of international standard setters in regard to the implementation of uniform research practices and International Conference on Harmonisation-Good Clinical Practices (ICH-GCP) adoption, often the global regulatory infrastructure has not kept pace with research needs.
Nevertheless, there is no evidence to suggest that the quality of the data and the overall research conducted outside the established pharmaceutical markets of North America and Western Europe is of lesser quality. In fact, from studies that have analyzed regulatory audit findings and error rates in reporting, the evidence is clear that there are not discernable differences in quality and, in some cases, that research quality from emerging countries exceeds that of established countries.
Table 2: Results of FDA Clinical Investigator Inspections 2000-08²

	No Action Required	Voluntary Action Required	Official Action Indicated	Total
Africa	41%	59%	0%	29
Asia/Pacific, other	63%	38%	0%	16
Australia/New Zealand	50%	50%	0%	4
Canada	33%	67%	0%	94
Central, Eastern Europe	42%	57%	1%	183
China	6%	94%	0%	17
India	40%	60%	0%	10
Japan	100%	0%	0%	1
Korea	0%	100%	0%	2
Latin America	31%	67%	3%	117
Middle East	18%	73%	9%	11
US	25%	65%	10%	4,014
Western Europe	25%	74%	1%	314
Total	1,248	3,157	407	4,812
VOI Consulting analysis of data found in FDA Investigational Human Drugs Clinical Investigator Inspection List, Retrieved May 18, 2009, from http://www.fda.gov/CDER/Offices/DSI/clinInvestList.htm

VOI Consulting analysis of data found in FDA Investigational Human Drugs Clinical Investigator Inspection List, Retrieved May 18, 2009, from http://www.fda.gov/CDER/Offices/DSI/clinInvestList.htm
One reason for the growing consistency in quality globally is that many emerging countries have adopted, or are in the process of implementing, regulations to ensure that clinical trials are conducted in a quality manner with an emphasis on ethics and participant safety.
CROs and research sponsors alike welcome these new regulations as they add certainty, consistency and confidence to the clinical research endeavor. ACRO, as the voice of the global CRO industry, pays acute attention to these regulatory developments ranging from Italy to India and Turkey to China.
Some of the more recent international regulatory developments have included:
ItalyThe Italian Authority (AIFA) adopted a Ministerial Decree that aims to define minimum requirements for CROs doing business in Italy. In part, the Decree requires the confirmation of educational, training, and experience requirements for clinical trial monitors.
India
India’s Central Drugs Standard Control Organization recommended that all clinical research organizations carrying out clinical trials on behalf of pharmaceuticals and medical device companies be required to register with the government.  Registration would cover all organizations, individuals, and companies with responsibility for managing or coordinating a clinical trial.  Registration, which would be valid for up to five years, would be granted on the condition that the individual or organization was thoroughly familiar with the product, protocol, content of participant consent forms, GCP guidelines, and other pertinent information.  The organizations would have to show that they have adequate resources and well-trained staff, and they would have to train staff on protocol adherence, informed consent, and responding to research subjects’ concerns.  The guidance is in the process of being finalized.
ChinaChina’s State Food and Drug Administration (SFDA) issued review and inspection standards for the “qualification confirmation” of institutions conducting clinical trials. A qualification confirmation involves more detailed scrutiny than the certification program for clinical study institutions.  Unlike certification guidelines, it includes inspection guidelines and checklists for confirming the qualifications of both clinical study institutions and individual departments within those institutions.
Singapore
The Singapore Health Sciences Authority (HSA) has launched a new inspection framework aimed at ensuring clinical trial sites comply with Good Clinical Practices (GCP).  A main focus is to verify the quality and integrity of the clinical trials data submitted to the agency.  GCP site inspections of contract research organizations and/or sponsor organizations will either be routine, triggered by complaints, or in response to a pre-marketing authorization approval application.
These developments are entirely consistent with the recommendations that accompanied the ACRO whitepaper. Specifically, that:
• The U.S Food and Drug Administration be provided sufficient resources to conduct inspections on a global basis in order to ensure that research quality is protected and improved around the world.
• All governments take measures to foster the development of a clinical research infrastructure and encourage clinical research participation.
• Overseas regulatory bodies recognize drug development as a global enterprise and that globalization leads to faster cures.
• All participants in clinical research—no matter where they live or the environment in which research takes place—be protected by the same level of safety and ethical considerations, and that they be afforded the same standard of care, including adherence to the GCP principles promulgated by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
Doing business on a global scale with myriad regulations is not a simple endeavor. Yet, CROs, research sponsors, and other stakeholders in the drug development process understand and accept that a strong international regulatory regime ultimately results in safe and effective therapies being brought market sooner.
About the Author
Doug Peddicord, PhD, serves as Executive Director of the Association of Clinical Research Organizations, Washington, DC.
References
1. Les Entreprises du Medicament (LEEM). (2008). The attractive position of France in International Clinical Research: 2008 survey assessed by Leem. Paris, France.
2. VOI Consulting analysis of data found in FDA Investigational Human Drugs Clinical Investigator Inspection List, Retrieved May 18, 2009, from http://www.fda.gov/CDER/Offices/DSI/clinInvestList.htm.

Parexel Reports Strong CRO Business

Parexel Reports Strong CRO Business
Drug Discovery & Development - January 26, 2010

NEW YORK (AP) - Shares of Parexel International Corp. climbed to an annual high after the pharmaceutical research contractor said it is winning more business than it previously expected, and raised its estimates for the fiscal year.
The Waltham, Mass., company said its drug development and late-stage clinical testing are doing more business in all regions. Both of those divisions took a hit as the economy slumped and drugmakers cut back on their spending. Parexel's orders were stronger than expected during the December quarter, as the company said it received $141 in orders for every $100 in orders it filled.
Analysts said the company previously expected a ratio of $125 in new orders per $100 that were filled.
In afternoon trading, Parexel stock rose $3.18, or 18 percent, to $20.72. Earlier it peaked at $21.10, the stock's highest price since October 2008.
Jefferies & Co. analyst David Windley said Parexel is benefiting from recent mergers among drugmakers, including last year's tie-ups between Pfizer Inc. and Wyeth, and Merck & Co. and Schering-Plough Corp., along with new partnerships, increased outsourcing, and more funding from biotechnology companies as the economy improves.
Windley said Parexel's comments about the drug development and late-stage businesses are "the first time we have heard such a positive statement regarding demand." He said the company is in position to report stronger profit and revenue growth than its rivals for the rest of the year.
Windley kept a "Buy" rating on Parexel shares.
Meanwhile, Raymond James analyst Alexander Draper upgraded the stock to "Outperform" from "Market Perform." Both analysts have price targets of $20 per share.
For the current fiscal year, which ends in June, Parexel raised its profit forecast to a range of $1 to $1.06 per share from 90 cents to $1 per share, and it now expects $1.13 billion to $1.15 billion in revenue, from $1.12 billion to $1.15 billion. It also gave a third-quarter outlook that was slightly above analyst expectations.
Date: January 26, 2010
Source: Associated Press

Breaking Down the Barriers

Breaking Down the Barriers
Mark Shapiro, Executive Director, Clinical Development, Clinipace Worldwide
Drug Discovery & Development - August 24, 2010

In traditional models, clinical trial functions such as project management and data management are conceptualized and operate independently, each with its unique budget, systems, and software. The independent systems and software make cross-talk among functions difficult and integration among applications expensive. In essence, no one sees the “big picture” of the study until long after the study begins. The end result is widespread duplication of effort and frequent miscommunication. Opportunities for efficiency and cost savings are lost as information is imperfectly transferred from one silo (and technology platform) to another, and quality of the overall effort suffers.
A new paradigm shift can transform outsourced clinical research and give rise to a new kind of contract research organization. The digital clinical research organization uses technology-optimized processes to improve trial performance, visibility, and coordination among all stakeholders. Clinical research and operations software integrates functions such as site selection and management, patient recruitment, project management, monitoring, data management, product safety, and biostatistics onto one platform.
The purpose of clinical data in a clinical trial is two-fold. First, data is used for the evaluation of the safety, tolerability, and efficacy of a drug, device, or biologic. Second, clinical trial data must provide for the accurate re-creation of events that took place during the trial. Because accurate and timely data are the foundation of any clinical study, the methodology used for data collection and management is of the utmost importance.

Many clinical research organizations still rely on methods and processes that originated in a paper-based research system with obvious challenges when those processes are forced onto a digital research system. Aside from the safety implications, data silos in a research study make cross-talk among functions difficult and integration among applications expensive.
The rise of the digital CRO
Through the use of technology, the digital CRO eliminates traditional barriers in the way clinical data is collected and stored by integrating all clinical research and operations software into one platform with roles and permissions-based access for all stakeholders. Instead of layering multiple technology-based tools such as electronic data capture (EDC) and clinical trial management programs onto existing methods, this approach is streamlining outsourced clinical research.
Combining integration and transparency of clinical research processes and clinical trial metadata fosters an unprecedented level of information sharing and analysis for better decision-making and improved efficiency to conduct a frictionless clinical trial. Although the current shift occurring in clinical research is fueled by technology, the people behind the software are the lifeblood of the transformation. The digital CRO is guided by the philosophy that technology is not an add-on to clinical trial processes; it is the backbone.
While technology alone can’t accomplish anything, when matched with the right vision, people and processes, technology can significantly enhance the efficiency, cost-effectiveness and safety of running a clinical trial.
Because every stakeholder involved in a digital CRO project works around the same hub, uses the same tools, and has instant access to the same information, those team members who are devoted primarily to monitoring, status tracking, and status reporting can focus their time on making strategic contributions through trouble-shooting, streamlining, and decision-making. The ability to strategize during a trial, rather than just managing the process—is a new concept in clinical research.
Because the electronic clinical systems of a digital CRO enable real-time trial enrollment visibility and confer the ability to identify and resolve data discrepancies remotely, the need for site visits is reduced. Clinical research associates (CRAs) on a technology-amplified study do not have to travel as much as they did in the traditional model. By employing a just-in-time monitoring approach (enabled by the digital CRO model), CRAs can obtain the information they need and travel to the site only when justified based on pre-specified criteria such as accumulation of data, queries, or other triggers such as a serious adverse event or protocol deviation.
The digital CRO model deploys CRAs more efficiently than the traditional model, facilitates identification of issues or problems, and enables earlier corrective actions, thereby reducing costs and enhancing study quality. Continuous remote monitoring of trial data and site performance via technology also helps to make visits more efficient and purposeful. Instead of having to spend days at a site reviewing vast amounts of information, a CRA can remotely identify issues that need to be addressed during the on-site visit.
Technology-enabled processes obviate the need for long meetings devoted solely to ensuring that all project stakeholders are abreast of the most current study status and issues. Likewise, rigid definition of functional areas within the project team is not required. The project team becomes more efficient because everyone is working with the same information.
All of the above-mentioned gains in efficiencies are associated with significant financial cost savings. In a current Phase 2 trial in which a sponsor used technology-amplified systems and processes, the sponsor estimates a 30% savings in the cost of the trial. This cost savings equates to more than a million dollars in operational costs through the simple process of deploying resources more efficiently.
ConclusionIn conclusion, digital CRO methods address the challenges highlighted by the FDA that are palpable to any stakeholder involved in product development. The adoption of digital CRO methods have brought about a shift to a new clinical research paradigm. Integration, collaboration, and transparency have helped to foster information sharing, enable efficient information analysis for better decision-making, and provide the environment for conduct of a frictionless clinical trial. This methodology, applied effectively on a widespread basis, is transforming the process, quality, cost, and outcomes of clinical research for the better.
Reference
1. Challenges and Opportunities Report - March 2004. U.S. Food and Drug Administration. Available at http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm. Accessed on August 24, 2010.

Finding the Right Formula

Finding the Right Formula
Rita C. Peters, Editorial Director
Drug Discovery & Development - September 01, 2010

Like other sectors of the drug discovery and development process, drug formulation and drug delivery research has been challenged with finding effective and economical routes to bringing a drug to its target. In a recent survey, Drug Discovery & Development asked contract research organizations (CROs) to identify trends in drug formulation and drug delivery. The responding CROs provide a range of services that meet the changing scientific and business needs of the market.
The looming “patent cliff” and tough economic conditions have changed the way drug companies approach research. Peter Thornton, senior vice president, head of product, technology and business development, Elan Drug Technologies, Dublin, Ireland, reports that more than two-thirds of products approved by the U.S. Food and Drug Administration (FDA) are for optimized or reformulated products.
Investors are less willing to gamble on drugs in discovery or preclinical phases, instead seeking compounds that are closer to clinical trials. Those companies that can generate early formulation data on molecules not only speed their research, but can improve the attractiveness of their offerings to potential investors.
The ability to provide integrated services to customers is becoming critical for management of timelines, according to WuXi AppTec Co., Ltd, Shanghai, China, which specializes in solid, oral dosage forms. The ability to generate critical preformulation data on drug molecules at an early stage enables decisions on the further development of drug candidates.
Technology has aided drug research in discovery, preclinical, and development phases, the respondents say. Thanks to advances in formulation techniques and new analytical methods, drugs that previously were difficult to formulate are now being taken into development, according to Charles River, Wilmington, Mass. The company offers formulation discovery and development activities for a range of dosage forms including preformulation investigations and screening, formulation development and validations, stability assessments, compatibility studies, and analytical chemistry services.
Generic and offshore competition, lower research productivity, and trimmed R&D budgets have provided sufficient incentive for drug and biotech companies to seek alternative routes for research efforts. Outsourcing can not only reduce fixed costs, but also buy expertise that may not be available internally.
“Increasing generic competition, declining R&D productivity, and rising drug development costs have pharmaceutical companies turning to CRO partners more now than in the past,“ says Linda M. Batykefer, marketing manager, ChemImage Corporation, Pittsburgh, Pa. “As the FDA pushes for quality by design (QbD) and process analytical technology, CRO companies will prove to be a valuable resource to pharmaceutical companies, guiding the creation of innovative solutions that satisfy these regulatory initiatives.”
Besides business decisions, scientific strategies play a vital role, not only in deciding to use a CRO, but selecting the best CRO for the task. The charts on pages 31-38 provide a snapshot of the services offered by the CROs that responded to the survey. Additional services can be found on http://www.dddmag.com/.
Science strategiesThe “fail early” theme holds true for drug formulation as researchers look to eliminate ineffective or unsafe compounds as soon as possible. Strategies include starting formulation studies earlier and re-examining dosing.
“There appears to be a push in pre-clinical testing to raise the amounts of drug dosed,” says David Barnes, CEO, Velesco Pharmaceutical Services, Plymouth, Mich. “More questions are being asked as to why the ‘maximum feasible dose’ cannot be raised. Velesco has invested considerable time and effort to develop better formulation systems for drugs in pre-clinical testing in order to help clients avoid such challenges from the regulatory authorities and to provide strong scientific evidence to support any ‘maximum feasible dose’ argument.” The company is developing a niche specialization in formulating benign, high drug loading products for use in pre-clinical studies.
Solubility was cited as a key scientific challenge as drug candidates become more and more insoluble.
“A large fraction of APIs under development are water insoluble or sparingly soluble. This is no longer as formidable a challenge as it used to be,” says Robert Lee, PhD, vice president, pharmaceutical development, Particle Sciences, Inc. (PSI), Bethlehem, Pa. “However, if the low solubility is coupled with hydrolytic or enzymatic lability, it can be very challenging to develop viable formulations. Additionally, if an API is highly potent and requires targeting, these constraints exacerbate the problem. Fortunately, these issues also represent opportunities for those able to overcome these hurdles.” PSI specializes in nano-based and rational solubility systems design approaches to formulation, with experience in topical and mucosal product development.
 The Biological Test Center in Irvine, Calif., which focuses on drug dosage formulations, reports that due to the insolubility of certain compounds, nanotechnology is moving to the forefront. For both commercial and experimental ophthalmic compounds, the company has seen an increase in testing of implantable drug coated or controlled-release delivery devices.
“The days when a simple salt of a molecule would provide all of the solubility and stability required appear to be behind us,” says Velasco’s Barnes. “This actually provides a great opportunity for formulators to save an otherwise good drug molecule from oblivion. There is also the added benefit of patent life extension to be gained by companies who invest in formulating these challenging compounds.”
No surprise, safety is a top concern. “The focus seems to be on new drug delivery methods that have fewer side effects and make administration to the patient easier,” says Batykefer. “Researchers are now looking at local or systemic delivery methods such as nasal, inhalation, and transdermal as alternatives to more traditional ones. As these administration routes present new challenges in drug design, development, and characterization, we will likely see many advancements made in this area.”
Companies also are looking at formulation as a way to alter toxicology profiles, change bioavailability, or deliver drugs to particular sites, according to Charles River. Time release formulations, depot formulations, formulations that are used with special devices to administer the drug, and use of nanoparticles to change the distribution of drugs in cells and tissues are becoming more and more complex.
“Drivers of the drug delivery market include customized oral drug delivery, depot injectable delivery, localized delivery of certain therapeutic agents or methods in which patient compliance is improved resulting in reduced health care costs,” says Elan Drug Technologies’ Thornton. In 40 years in the drug delivery business, the company has brought 36 client drugs to market, offering bioavailability enhancement technologies and customized oral drug technologies.
Some challenges appear in the formulation stage. BioConvergence LLC, Bloomington, Ind. notes molecules in the development pipeline are becoming more sensitive to the stresses of formulation and storage conditions, especially as the presence of biotech molecules increases. Company scientists have worked on both small and large molecules, sterile injectable formulations, lyophilized products, oral and topical formulations, and potent and cytotoxic products.
Stason Pharmaceuticals, Irvine, Calif., focuses on products requiring high containment manufacturing, cytotoxic products as well as products that are difficult to manufacture.
A key trend, according to the company, is that the FDA has increased its scrutiny of the active pharmaceutical ingredients (API) particle size and their impact on the finished product solubility and has mandated testing for residual solvents in finished products. Statson offerings include solubility and stability evaluations, prototype development, comprehensive screening of raw materials and excipients, formulation optimization, and finalization.
With the ongoing shift toward proteins and large molecules, MPI Research, Inc., Mattawan, Mich., has increased its expertise, says Alan Breau, PhD Vice President Bioanalytical/Analytical. “In order to respond to this trend MPI has added PhD-level protein chemists to its formulations staff. We recognize the unique formulation and handling challenges required in the preparation of protein versus small molecule dose formulations.” The company develops and validates methodologies for small and large molecules in a wide variety of biomatrices.
New paradigmsWhether in partnership or on a contractual basis with a drug formulation company, drug companies seek both lab assistance and also expertise in new research arenas.
—The Editors

Mylan Gets FDA Nod for HIV Treatments

Mylan Gets FDA Nod for HIV Treatments
Drug Discovery & Development - January 20, 2011

PITTSBURGH (AP) — Drug developer Mylan Inc. said that the Food and Drug Administration tentatively approved the company's pediatric HIV treatment.
The company said the Lamivudine and Zidovudine tablets will be eligible for purchase outside the U.S. in certain developing countries.
Date: January 20, 2011
Source: Associated Press

Health Agencies Expediting Telaprevir Reviews

Health Agencies Expediting Telaprevir Reviews
Drug Discovery & Development - January 20, 2011

CAMBRIDGE, Mass. (AP) - Vertex Pharmaceuticals Inc. said that regulators in the U.S. and Canada will speed their reviews of its drug candidate telaprevir, meaning the hepatitis C therapy could be approved months earlier than usual.
Vertex said the Food and Drug Administration will do a six-month priority review on telaprevir, meaning the agency expects to make a decision by May 23. Typical FDA reviews last about 10 months, starting from the date the drug maker files for approval.
The Therapeutic Product Directorate of Health Canada will take six to nine months to make its decision on telaprevir, Vertex said. Standard reviews in Canada take about a year and a half.
Telaprevir is already receiving an accelerated review in Europe. Analysts believe Vertex could get billions of dollars in annual revenue from telaprevir, the first in what could be a series of new treatments for hepatitis C.
Telaprevir and Merck & Co.'s drug boceprevir are more effective than older therapies in controlling the viral liver disease.
Date: January 20, 2011
Source: Associated Press

Allos Reports New Folotyn Data

Allos Reports New Folotyn Data
Drug Discovery & Development - January 20, 2011

WESTMINSTER, Colo. (AP) - Allos Therapeutics Inc. said its lymphoma drug Folotyn helped some patients who had no response to previous therapies.
The results were based on a new analysis of a midstage clinical trial that ended in 2009, the company said late Wednesday. Out of 69 patients who had no response to their most recent treatment - meaning their tumors did not shrink at all - 17 experienced a response while they were being treated with Folotyn. The analysis also found that out of 17 patients who had no response to any previous therapy, five responded to Folotyn.
Folotyn was approved in January 2010 as a treatment for relapsed peripheral T-cell lymphoma. The company said the patients who responded to Folotyn had median survival of 14.5 months, and median survival before disease progression was 3.5 months.
The most common serious side effects of Folotyn treatment were anemia, low levels of blood platelets, lower white blood cell count, and inflammation of the mucous membranes.
The results were published in the Journal of Clinical Oncology.
Date: January 19, 2011
Source: Associated Press

Levomilnacipran Flunks Latest Trial

Levomilnacipran Flunks Latest Trial
Drug Discovery & Development - January 20, 2011

NEW YORK (AP) - Forest Laboratories Inc. said its depression treatment levomilnacipran failed in a late-stage clinical trial, as the drug was no more effective than a placebo at treating depression.
Forest and its partner, French drugmaker Pierre Fabre Medicament, said the patients treated with levomilnacipran and patients treated with placebo had similar results, and the difference between them was not statistically significant. In the trial, 362 patients were treated with 40 milligrams to 100 milligrams of levomilnacipran per day or a placebo. The 11-week study compared the change in patients' symptoms on a clinical rating scale.
The companies said 8 percent of the levomilnacipran patients left the study due to side effects, compared to 2.2 percent of patients who took the placebo. The most common side effects of treatment with levomilnacipran were nausea and headache. Forest and Pierre Fabre are running two other late-stage trials of the drug, and they expect results from those studies in the second half of 2011.
Date: January 19, 2011
Source: Associated Press

GSK And Prosensa Begin Phase 3 DMD Trial

GSK And Prosensa Begin Phase 3 DMD Trial
Drug Discovery & Development - January 19, 2011

GlaxoSmithKline and Prosensa announced that the first patient has commenced treatment in the Phase 3 clinical study investigating GSK2402968, in ambulant boys with Duchenne Muscular Dystrophy (DMD), who have a dystrophin gene mutation amenable to an exon 51 skip (up to 13% of boys with DMD). Commencement of this study confirms previously announced plans to progress this asset into Phase 3.
This randomised, placebo controlled study will enroll 180 patients, from up to 18 countries, and is currently the most advanced ongoing study for this rare, severely debilitating, neuromuscular disease.
The study is designed to assess the efficacy and safety of GSK2402968 6mg/kg, once weekly, for 48 weeks in ambulant boys over 5 years of age with DMD, compared to placebo. The primary efficacy endpoint is a measure of muscle function using the six minute walking distance (6MWD) test.
“The commencement of this Phase 3 study is an important milestone,” said Dr Philippe Monteyne, Head of Development and Chief Medical Officer for GSK Rare Diseases. "Currently, there is no approved treatment to alter the course of DMD – a disease that puts boys in wheelchairs and often leads to death in early adulthood.”
“We are very pleased with this achievement. It is another step forward in our joint fight against Duchenne,” said Dr Giles Campion, Chief Medical Officer of Prosensa. “If the results of this study are positive, we hope it will lead to an approved treatment option for the thousands of young people worldwide living with this devastating disease.”
Date: January 19, 2011
Source: GlaxoSmithKline 

BRIM3 Trials Shows Significant Benefit

BRIM3 Trials Shows Significant Benefit
Drug Discovery & Development - January 19, 2011

Genentech, a member of the Roche Group, announced that BRIM3, a Phase 3 clinical study of RG7204 (PLX4032), met its co-primary endpoints showing a significant survival benefit in people with previously untreated BRAF V600 mutation-positive metastatic melanoma. Study participants who received RG7204 lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to participants who received dacarbazine, the current standard of care. RG7204 is a potential first-in-class medicine designed to selectively inhibit the mutated BRAF protein found in about half of all cases of metastatic melanoma – the most aggressive and deadliest form of skin cancer. The safety profile was generally consistent with previous RG7204 studies.
“For the first time, a personalized investigational medicine, RG7204, has shown a significant survival benefit in metastatic melanoma. This is an important advance for people with the BRAF V600 mutation-positive form of the disease who have had extremely limited treatment options,” said Hal Barron M.D., chief medical officer and head, Global Product Development.
Based on these interim analysis results, patients on the control arm of the study will have the option to crossover to receive RG7204.
The most frequent Grade 3 adverse event was skin related and included cutaneous squamous cell carcinoma, a common skin cancer treated by local excision. Additionally, generally mild and reversible increases in liver enzymes (GGT, ALT, AST, alkaline phosphatase, and bilirubin) were observed in some patients. The most common adverse events were rash, photosensitivity, joint pain, hair loss and fatigue.
Full data will be presented at a medical meeting later this year.
Genentech is now working closely with global health authorities to expand the recently announced RG7204 Patient Access Program (PAP). The PAP will be extended to include people with previously untreated, BRAF V600 mutation-positive metastatic melanoma (first line).
RG7204 exemplifies Genentech’s personalized healthcare approach using biomarkers and diagnostic tools to identify the right medicine for the right patient.  RG7204 is being co-developed with an investigational diagnostic test, the cobas® 4800 BRAF V600 Mutation Test  from Roche Molecular Diagnostics, to identify patients whose tumors carry the mutated BRAF V600 gene.
Date: January 19, 2011
Source: Genentech 

Alexza Filing New Application with FDA

Alexza Filing New Application with FDA
Drug Discovery & Development - January 19, 2011

MOUNTAIN VIEW, Calif. (AP) - Shares of Alexza Pharmaceuticals Inc. sank after the company said it will file a new application for its drug candidate Adusuve Staccato in July.
Alexza expects the Food and Drug Administration to take six months to review its new submission. That means the agency could make a decision on Adusuve Staccato - the company's lead program - in early 2012.
In morning trading, shares of Alexza dropped 27 cents, or 16.2 percent, to $1.40.
Adusuve Staccato is an inhaled drug that is designed to treat agitation caused by schizophrenia or bipolar disorder. The FDA declined to approve the drug in October, citing concerns about the effects of the Staccato inhaler device has on patients' lungs. The agency also raised concerns about manufacturing issues. The company said Tuesday that the agency wants additional data related to the effects of the Staccato device on humans.
Alexza said the FDA said it wants it to develop a risk evaluation strategy and determine a way to identify patients who are at risk for pulmonary side effects.
Alexza is developing several other drugs that are administered through the Staccato device, including treatments for migraine headaches, panic attacks, severe pain, and insomnia.
Date: January 18, 2011
Source: Associated Press

Two New HCV Drugs Approaching Market

Lauran Neergard
Drug Discovery & Development - January 19, 2011

WASHINGTON (AP) - There's new hope for an overlooked epidemic: Two powerful drugs are nearing the market that promise to help cure many more people of liver-attacking hepatitis C - even though most who have the simmering infection don't know it yet.
Surprisingly, two-thirds of hepatitis C sufferers are thought to be baby boomers who've harbored since their younger, perhaps wilder, years a virus that can take two or three decades to do its damage.
What could be a treatment revolution is spurring the government to consider if it's time to start screening aging baby boomers for hepatitis C, just like they get various cancer checks.
"We're entering a whole new era of therapy," says Dr. John Ward, hepatitis chief at the Centers for Disease Control and Prevention. "We really want to begin that clarion call for action for this population who's at risk."
Today's two-drug treatment for hepatitis C cures only about 40 percent of people with the most common variety of the virus, and causes some grueling side effects. Now major studies show that adding a new drug -either Vertex Pharmaceuticals' telaprevir or Merck & Co.'s boceprevir - can boost those cure rates as high as 75 percent. And they allow some people to cut treatment time in half, to six months, thus lessening how long they must deal with those side effects.
If the Food and Drug Administration approves the drugs - a decision widely expected this summer - they would be the first that work by directly targeting the hepatitis C virus. Specialists draw comparisons to the early 1990s when potent combination therapies emerged to treat AIDS. Many recently diagnosed patients are postponing therapy to await these new drug cocktails in hopes of a better chance at a faster cure, says Dr. Paul Pockros, hepatology chief at the Scripps Clinic in La Jolla, Calif., who helped test telaprevir.
However, the bigger impact could come if more people get tested for hepatitis C, a blood-borne virus. It's often stigmatized as a risk only to people who inject illegal drugs. But the virus could have begun festering from a blood transfusion before 1992, when testing of the blood supply began.
Lapses in infection control in health facilities still occasionally expose people today. So could even a one-time experiment with drugs way back in college, something doctors are reluctant to ask a now middle-aged, button-downed patient to reveal, says Ward.
"It cuts across every segment of society," adds Dr. Arun Sanyal of Virginia Commonwealth University, past president of the American Association for the Study of Liver Diseases. "I can tell you our hepatitis C treatment clinic is a great social equalizer."
About 3.2 million Americans, and 170 million people worldwide, have chronic hepatitis C. In the U.S., new infections have dropped dramatically - although the disease's toll is rising as people infected decades earlier reach ages where their livers start showing damage. Hepatitis C already is a leading cause of liver transplants, and it kills about 12,000 U.S. patients a year, a number expected to triple within 20 years.
Most people find out they're infected like Brian Graham of Briarcliff Manor, N.Y., during a routine check-up that spotted elevated liver enzymes. He'd never heard of hepatitis C and had no obvious risk factors. But tests showed the virus had begun to scar his liver. So over the last decade he tried three rounds of traditional treatments, with increasingly tough side effects, to no avail.
"I didn't want to die of liver disease or cancer or suffer the prospect of having to tee up for a liver transplant. Scary stuff," says Graham, now 56.
Enter the new drugs. They work by blocking an enzyme named protease that's key for the virus to reproduce. But they must be taken together with standard medications - ribavirin pills plus injections of interferon-alpha - that are thought to boost the immune system.
According to studies presented at a recent medical meeting, 67 percent to 75 percent of patients given treatment including either boceprevir or telaprevir, respectively, had what doctors call a cure. That's defined as no sign of the hepatitis C virus six months after their last dose. Importantly, only about a quarter of black patients are helped by standard therapy but adding one of the new drugs more than doubled their cure rates.
People getting their first-ever treatment did best, but the studies also found improvements in hard-to-treat patients like Graham.
"The fourth time did the trick," says Graham, who volunteered for an early telaprevir study and says he's been hepatitis-free for three years.
The new drugs do add side effects to the flulike symptoms and other complaints of existing treatment. Telaprevir's main risk is a rash that is sometimes severe, and boceprevir's is anemia.
"The future looks very bright beyond telaprevir and boceprevir," notes Dr. Fred Poordad of Cedars-Sinai Medical Center in Los Angeles, who has studied both drugs and consults for several companies. He points to additional drugs in earlier-stage testing that promise to target more types of hepatitis C and perhaps eventually allow for pill-only, interferon-free treatment.
Manufacturers haven't said how much the new drugs will add to the price of treatment that already can cost $30,000, albeit far cheaper than a liver transplant.
A stickier issue: Not everyone suffers serious liver damage and it's hard to predict who will, raising questions about exactly who needs treatment even as drug companies help push for more screening."
That's a concern, acknowledges Jeff Levi of the nonprofit Trust for America's Health, also a screening proponent. But when to treat is a doctor-patient decision, and "anyone with chronic infection you do want to be monitoring so you can intervene at the right moment," he adds.
Plus, people with hepatitis C should avoid alcohol and consider other liver-protection steps - and know how to avoid infecting others, he stresses.
Stay tuned: The CDC has begun a study at four hospitals - in New York, Detroit, Houston and Birmingham, Ala. - to see if a one-time hepatitis C test for baby boomers makes sense. Among the boomers, black men in their 50s are at particular risk. CDC plans new guidelines next year.
Meanwhile, "start that conversation" at a routine doctor's visit by asking about hepatitis C risks and testing, Ward advises boomers.
Date: January 18, 2011
Source: Associated Press

New Study Finds Crucial Inflammatory Protein

New Study Finds Crucial Inflammatory Protein
Drug Discovery & Development - January 17, 2011

Scientists have identified a protein that acts as a "master switch" in certain white blood cells, determining whether they promote or inhibit inflammation. The study, published in the journal Nature Immunology, could help researchers look for new treatments for diseases such as rheumatoid arthritis that involve excessive inflammation.
Inflammatory responses are an important defence that the body uses against harmful stimuli such as infections or tissue damage, but in many conditions, excessive inflammation can itself harm the body. In rheumatoid arthritis, the joints become swollen and painful, but the reasons why this happens are not well understood.
Cells of the immune system called macrophages can either stimulate inflammation or suppress it by releasing chemical signals that alter the behaviour of other cells. The new study, by scientists from Imperial College London, has shown that a protein called IRF5 acts as a molecular switch that controls whether macrophages promote or inhibit inflammation.
The results suggest that blocking the production of IRF5 in macrophages might be an effective way of treating a wide range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, lupus, and multiple sclerosis. In addition, boosting IRF5 levels might help to treat people whose immune systems are compromised.
Researchers from Imperial College London previously developed anti-TNF treatments, a class of drug that is widely used as a treatment for rheumatoid arthritis. The drugs target TNF, an important signalling chemical released by immune cells to stimulate inflammatory responses. However, about 30 per cent of patients don't respond to anti-TNF drugs, so there is a serious need to develop more widely effective therapies.
Dr Irina Udalova from the Kennedy Institute of Rheumatology at Imperial College London, the senior researcher on the study, said:
"Diseases can affect which genes are switched on and off in particular types of cells. Understanding how this switching is regulated is crucial for designing targeted strategies to suppress unwanted cell responses.
"Our results show that IRF5 is the master switch in a key set of immune cells, which determines the profile of genes that get turned on in those cells. This is really exciting because it means that if we can design molecules that interfere with IRF5 function, it could give us new anti-inflammatory treatments for a wide variety of conditions."
Gene association studies have linked variations in the gene that encodes IRF5 with an increased risk of autoimmune diseases. This led Dr Udalova and a PhD student in her lab, Mr Thomas Krausgruber, to investigate what role the protein plays in controlling inflammation.
They used engineered viruses to introduce extra copies of the IRF5 gene in human macrophages grown in the laboratory, making the cells produce more IRF5. When they did this to macrophages with anti-inflammatory characteristics, it made them switch to promoting inflammation. When they blocked IRF5 in pro-inflammatory macrophages using synthetic molecules, this reduced the cells' production of signals that promote inflammation. The researchers also studied genetically modified mice that were unable to produce IRF5. These mice produced lower levels of chemical signals that stimulate inflammation.
IRF5 seems to work by switching on genes that stimulate inflammatory responses and dampening genes that inhibit them. It can either do this by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on. Dr Udalova's group are now studying how IRF5 works at a molecular level and which other proteins it interacts with so that they can design ways to block its effects.
Date: January 16, 2011
Source: Imperial College London 

Domain and Merck Sign mGluR4 Agreement

Domain and Merck Sign mGluR4 Agreement
Drug Discovery & Development - January 17, 2011

Domain Therapeutics announced that an exclusive development and licensing agreement with Merck Serono, a division of Merck KGaA was signed to develop metabotropic glutamate receptor 4 (mGluR4) Positive Allosteric Modulator (PAM) drugs targeting Parkinson’s disease and other neurodegenerative diseases.

Domain Therapeutics will contribute optimized compounds that have been developed from its proprietary chemical series. Under the terms of the agreement, the company will receive €2 million in upfront payment and research funding, and is eligible for up to €132 million in milestones for the first two products, as well as undisclosed royalties.

“This agreement is a validation of Domain Therapeutics’ business model of addressing difficult GPCRs and partnering compounds, with a significant deal, at an early stage of development,” said Pascal Neuville, CEO, Domain Therapeutics. “Merck Serono is known to set very high standards for the compounds it is licensing and this deal is a demonstration of the quality of our work. We anticipate that this agreement will enable us to sign further deals of this kind.”

"We are pleased to have the opportunity to work with Domain Therapeutics, which has developed great expertise in the GPCR area," said Bernhard Kirschbaum, Executive Vice President for Global Research and Development at Merck Serono. "This partnership with Domain Therapeutics reflects our long-term commitment to develop new treatments for neurodegenerative diseases."

mGluR4 is a glutamate receptor, member of the G-Protein Coupled Receptor (GPCR) family and is believed to be a potential therapeutic target for Parkinson’s disease. Allosteric modulation of mGluR4 receptors is thought to exert regulatory activity on glutamate-mediated neurotransmission.
Date: January 17, 2011
Source: Domain Therapeutics

New Study Backs Combination Cancer Therapy

New Study Backs Combination Cancer Therapy
Drug Discovery & Development - January 17, 2011

A new study by Ohio State University cancer researchers provides a rational for treating breast cancer by combining two kinds of targeted agents, one that inhibits an overactive, cancer-causing pathway in cancer cells and one that reverses changes that silence genes that normally prevent cancer. Both types of agents are currently available and being evaluated individually in clinical trials, the researchers note.
The findings, published online in the journal Cancer Research, show that abnormal activation of the PI3K/AKT signaling pathway leads to the silencing of a number of tumor-suppressor genes that regulate cell proliferation, survival and motility and angiogenesis.
The laboratory and animal study also shows that combining an agent that inhibits PI3K and a drug that reverse the epigenetic changesthat cause gene silencing significantly slows tumor growth.
“The link we have uncovered between PI3K/AKT signaling and epigenetic silencing offers a new therapeutic strategy for breast cancer that combines a PI3K/AKT inhibitor and agents that target epigenetic changes,” says study leader Tim H-M Huang, professor of molecular virology, immunology and medical genetics at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
“Our studies show that, in models, these agents work together synergistically to reverse gene silencing and suppress cancer-cell growth, suggesting that combining these targeted agents might improve breast-cancer therapy.”
Cancer development typically involves the abnormal activation of genes that regulate cell growth and the silencing of genes that normally prevent cancer development. The activation of one or more “oncogenes” and the silencing of tumor-suppressor genes are usually considered separate events that together lead to cancer. This and earlier studies led by Huang show that the two events are sometimes linked.
Huang and his colleagues are now planning a clinical trial for patients with metastatic breast cancer that will investigate the use of combined targeted drugs.
Date: January 13, 2011
Source: Ohio State University http://www.osu.edu/

Omthera Announces Epanova Trial Results

Omthera Announces Epanova Trial Results
Drug Discovery & Development - January 17, 2011

Omthera Pharmaceuticals, Inc., a privately-held emerging specialty pharmaceuticals company, announced data from its ECLIPSE trial (Epanova Compared to Lovaza In a Pharmacokinetic Single-dose Evaluation), designed to evaluate the bioavailability of Epanova, the company’s lead compound for the treatment of very high triglycerides (≥500 mg/dL), in comparison to Lovaza, the leading prescription Omega 3. Epanova is an Omega 3 fatty acid compound containing a novel formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
The primary objective of the 54 subject, randomized, open-label, four-way cross-over pharmacokinetics (PK) study, was to compare the bioavailability of EPA and DHA over 24 hours from either Epanova and Lovaza as single 4-gram doses with low- or high-fat diets.
Data from the trial showed that the bioavailability of Epanova was dramatically superior to Lovaza. Specifically, the plasma level of EPA+DHA in subjects on a low-fat diet who received Epanova was over four times higher than those given Lovaza. Epanova also demonstrated significantly higher EPA+DHA levels than Lovaza on a high-fat diet. In a separate analysis, Epanova demonstrated a 13-fold increase in bioavailability of EPA over Lovaza in subjects consuming a low-fat diet in this study.
Commenting on today’s news, Dr. Michael Davidson, Chief Medical Officer and co-founder of Omthera Pharmaceuticals, noted, “We are extremely pleased with the very impressive results generated by this head-to-head comparative bioavailability study, which, for the first time, demonstrate that Epanova, a free fatty acid (FFA) form of EPA and DHA, has significantly better bioavailability than Lovaza, an ethyl ester EPA and DHA product, in subjects on a high-fat diet; and dramatically higher bioavailability in subjects consuming a low-fat diet.  The ECLIPSE study demonstrates that Lovaza is poorly absorbed in patients on a low-fat diet. We believe that this finding will have significant clinical importance because patients with severe hypertriglyceridemia should be maintained on a low-fat diet.
The data from this study clearly demonstrates that Epanova will provide superior blood levels of Omega 3’s with both low- and high-fat diets.”
“The results of Omthera’s ECLIPSE study confirm the superior absorption profile of Epanova versus the only currently marketed prescription Omega 3 therapy, and is the last step in our development program prior to initiating a pivotal Phase 3 trial evaluating Epanova in patients with very high triglycerides, which we aim to begin during the first quarter of 2011,” said Jerry Wisler, President, Chief Executive Officer, and co-founder of Omthera.
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 a member of Omthera’s Scientific Advisory Board, stated, “While studies have shown that FFA forms of Omega 3 have superior bioavailability versus others, including the currently prescribed ethyl ester formulation found in Lovaza, the positive PK results generated by Omthera’s ECLIPSE study are even more notable than I had expected.  The data strongly suggest that Epanova could ultimately represent an important improvement in the management of patients suffering from severe hypertriglyceridemia. I look forward to the continued development of this novel prescription Omega 3.”
Dr. Davidson concluded, “The dramatic rise in obesity over the last 10 to 20 years has led to a concomitant increase in triglyceride levels among the population and a shift in clinician’s awareness to the critical role that high triglyceride levels have as a predictor of cardiovascular events.  Since patients with very high triglycerides should be placed on a low-fat diet, an Omega 3 product that is better absorbed with a low-fat diet, as Epanova has demonstrated in the ECLIPSE study, would likely be a significant improvement over the ethyl ester Omega 3s.”
Date: January 7, 2011
Source: Omthera Pharmaceuticals, Inc. 

GPCR Biased Ligands for Better Drugs

GPCR Biased Ligands for Better Drugs
Michael W. Lark, PhD, CSO and SVP, Research, Jonathan Violin, PhD, Head, Biology, David Soergel, M.D., VP and Head, Clinical Development, Trevena, Inc., King of Prussia, PA
Drug Discovery & Development - January 01, 2011

G-protein coupled receptors (GPCRs) are the most tractable drug discovery targets in the pharmaceutical industry. Classical GPCR drugs either activate or inhibit all of the intracellular signaling pathways at the receptor, which mediate both beneficial and adverse effects. Trevena is developing a pipeline of programs with enhanced therapeutic properties derived from selective activation of GPCR signaling. Trevena’s molecules are biased ligands, that selectively activate only those biological pathways at the receptor associated with beneficial effects.
There are significant opportunities to improve upon currently marketed GPCR drugs because many have limited efficacy and undesirable adverse effects.  Trevena’s scientific founders discovered that both G-proteins and beta-arrestins  activate unique intracellular pathways responsible for separable biological responses , and these responses can be independently modulated using biased ligands . Trevena has translated these findings into a proprietary drug discovery platform, and has identified biased ligands to multiple GPCRs. The company is currently testing its first novel biased ligand in humans. TRV120027 is being developed for the treatment of acute heart failure and Phase 1 clinical studies were successfully completed earlier this year, with a Phase 2 clinical trial expected to begin in 2011.
TRV120027 is a beta-arrestin-biased ligand that blocks angiotensin-mediated G-protein signaling at the AT1R receptor while simultaneously stimulating AT1R-specific beta-arrestin signaling . As presented at the 2010 Heart Failure Society of America meeting, TRV120027 possesses a unique set of properties in vivo, including cardiac performance enhancement, systemic blood pressure reduction, and a short half-life. TRV120027 has also shown cardiac unloading activity while preserving renal function, which is a key feature for a potential therapy for acute heart failure.
In addition to TRV120027, Trevena’s platform continues to deliver a portfolio of novel biased ligands, targeting receptors involved in CNS and inflammatory diseases. The two most advanced programs target receptors involved in pain control and novel biased ligands are currently being optimized to deliver transformational clinical candidates with improved therapeutic indices.
References
1. Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science.2005;308:512-517.
2. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physio. 2007;69:483-510.
3. Wei H, et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci 2003;100:10782-10787.
4. Violin JD, DeWire, S.M., Yamashita, D., Rominger, D.H., Nguyen, L., Schiller, K., Whalen, E.J., Gowen, M. and Lark, M.W.t al.  J. Pharm and Exp. Therap. 2010;335:1-8.

NVC-422 Effective Against Superbug

NVC-422 Effective Against Superbug
Drug Discovery & Development - January 06, 2011

NovaBay Pharmaceuticals, a clinical stage biotechnology company developing first-in-class, anti-infective compounds for the treatment and prevention of antibiotic-resistant infections, announces that in tests conducted at a third-party laboratory, NovaBay's lead Aganocide, NVC-422 has shown in vitro activity against the "superbug" New Delhi Metallo-beta-lactamase-1 (NDM-1)-encoded Klebsiella pneumoniae at a very low concentration of 2 mg/mL. In comparison, Imipenem, which is a mainstay antibiotic for the treatment of antibiotic-resistant bacterial infections, is not effective against NDM-1-encoded strains.
NovaBay currently is engaged in testing additional strains of E. coli and K. pneumoniae encoded with NDM-1 gene. The company previously reported that NVC-422 was effective in vitro against resistance phenotypes of E. coli and K. pneumoniae, including extended-spectrum beta-lactamase (ESBL) and multidrug-resistant (MDR) strains. NovaBay intends to publish and present the full data set at the upcoming Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
K. pneumoniae and E. coli have been identified as a cause of severe infections, sepsis and possibly death. In a number of non-systemic/topical opportunities of interest to NovaBay's development, both these superbugs are major risk factors. These include catheter-associated urinary tract infections (UTIs); respiratory tract infections, including those caused by cystic fibrosis; and wound infections, including venous stasis, pressure ulcers and diabetic ulcers.
Dr. Ron Najafi, CEO of NovaBay Pharmaceuticals, said, "We were very excited to see the in vitro activity results of NVC-422 against NDM-1 strains. In fact, we have collected data indicating that NVC-422 is also effective in vitro against all six highly resistant pathogens know as ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter which are the cause of much of the hospital-associated Infections today. We intend to translate this activity into products that will benefit patients in need. Both UTI and chronic non-healing wounds will be the future breeding ground for NDM-1 producing bacteria."
NovaBay is currently engaged in a Phase 2 human trial for urinary catheter blockage and encrustation (UCBE) leading to urinary tract infections, and the company and its partner Galderma S.A. are engaged in the clinical development of its lead compound for the treatment of impetigo, a highly contagious infection with potential benefit in chronic wound care management.
Date: January 6, 2010
Source: NovaBay Pharmaceuticals

CeNeRx Starts Trial of Depression Treatment

CeNeRx Starts Trial of Depression Treatment
Drug Discovery & Development - January 06, 2011

CeNeRx BioPharma, Inc., reported that it has initiated a Phase 2 trial of its new formulation of TriRima, the company’s novel antidepressant in development as monotherapy for treatment resistant depression.
TriRima is a member of a novel class of drugs known as RIMAs, or reversible and selective inhibitors of monoamine oxidase A (MAO-A).  MAO inhibitors achieve superior “triple-action” antidepressant efficacy by elevating the levels of all three of the key neurotransmitters that positively affect mood.  However, older MAO inhibitors have been limited by their potential to cause serious cardiovascular side effects when foods containing the naturally occurring substance tyramine are consumed.
TriRima is designed to achieve the efficacy of the MAO inhibitor class while reducing or eliminating the risk of these food-associated effects.  In a recently reported “tyramine challenge” study, subjects receiving the new formulation of TriRima showed no signs of any negative effects, even after being exposed to large amounts of tyramine.  These positive results further confirmed the good safety profile demonstrated by TriRima in Phase I studies.
The Phase 2 trial is a double blind, placebo-controlled study designed to assess the efficacy of TriRima administered twice daily as monotherapy in patients with treatment resistant depression.  Secondary objectives include evaluating TriRima’s safety and tolerability and assessing its pharmacokinetic profile.  CeNeRx expects to enroll 360 patients in the study, which is being conducted at multiple centers in the U.S.
“We are eager to test the efficacy of our promising new formulation of TriRima in treatment resistant depression, and we are delighted that our Phase 2 trial is now enrolling patients,” said Daniel Burch, MD, Chief Medical Officer of CeNeRx.  “The new formulation of TriRima has demonstrated excellent safety in multiple studies to date, and we believe that it has the potential to become the first agent to achieve the triple action efficacy of MAO inhibitor drugs without their limiting side effects.”
The modified release formulation of TriRima has major advantages over the version used in earlier studies.  In addition to displaying excellent pharmacokinetic properties, the dosing frequency has been reduced to one tablet administered once or twice daily.
“TriRima addresses a large unmet medical need—currently a substantial proportion of patients with major depression do not receive adequate relief from their therapy,” noted Barry Brand, Chief Executive Officer of CeNeRx.  “TriRima has the potential to be the first option that provides these patients superior efficacy and a good safety profile as monotherapy, and we look forward to advancing the Phase 2 trial in the coming year.”
Date: January 6, 2010
Source: CeNeRx BioPharma, Inc. 

MultiStem Trial Wraps Up Enrollment

MultiStem Trial Wraps Up Enrollment
Drug Discovery & Development - January 06, 2011

Athersys, Inc. announced that it has completed patient enrollment of the single dose arm of a clinical study involving administration of MultiStem to patients being treated for leukemia or other blood born cancers. The study involves administration of a single or multiple doses of MultiStem, an allogeneic cell therapy product, to patients following radiation therapy and a donor derived hematopoietic stem cell transplant. Patients receiving such transplants are typically at risk for Graft-Versus-Host Disease (GVHD), as well as other complications, such as tissue damage from the radiation and chemotherapy treatments that are conducted prior to the transplant. Initial results of safety information from the single dose arm of this trial are expected to be announced following the completion of patient evaluation periods and subsequent analysis of data.
GVHD is one of the major limitations of allogeneic donor derived hematopoietic stem cell transplants. This complication is a significant cause of morbidity and mortality and is thought to be initiated by activation of donor immune cells, such as activated T-cells, that attack host cells in the transplant recipient as foreign tissue. Acute GVHD is associated with damage to the liver, skin, gastrointestinal tract and other tissues. Moderate to severe GVHD Grades II-IV occurs in 30-50% of matched related hematopoietic stem cell transplants (HSCT) and 50-70% of matched unrelated donor recipients. Severe GVHD requires treatment using intense immunosuppression with steroids and additional agents, and patients may develop severe infections as a result of such immunosuppression. An agent or cell therapy that could prevent the incidence and/or severity of GVHD without increasing relapse or infectious risk in HSCT patients would provide substantial benefits.
"Despite significant advances in recent years, treatment of leukemia and other cancers of the blood and immune system is a substantial clinical challenge. Radiation and chemotherapy followed by hematopoietic stem cell transplantation remains the standard of care in many areas. Unfortunately, many patients experience complications from treatment, such as GVHD, that can be debilitating or life threatening," commented Dr. Robert Deans, Senior Vice President of Regenerative Medicine of Athersys. "Based on results from preclinical studies conducted in coordination with independent labs, we believe that MultiStem has the potential to reduce the incidence and severity of GVHD and other complications and improve patient outcomes. This Phase I safety study represents an important step in the development of MultiStem for this condition, and we look forward to evaluating the data from the trial upon completion of the appropriate follow up visits."
The Phase I clinical trial is an open label, multi-center dose escalation trial evaluating the safety and maximum tolerated dose of a single or multiple dose administration of allogeneic MultiStem delivered intravenously following standard allogeneic hematopoietic stem cell transplant. Patients enrolled in the study receive either a low, medium or high dose of MultiStem, and are being evaluated against current standard of care. Treatment of the final patient for the single dose arm occurred December 30, 2010, consistent with the previously stated goal of completing enrollment prior to year-end, while enrollment in the multiple dose arm will continue and is intended to be completed in 2011. The study is being conducted at multiple bone marrow transplant centers in the United States, including Oregon Health & Science University Medical Center, Texas Transplant Institute, University Hospitals Case Medical Center, University of Pennsylvania, Mayo Clinic Arizona, and several other sites.
In September 2010, Athersys received orphan drug designation from the U.S. Food and Drug Administration for the prevention of GVHD. Orphan drug designation, which is intended to encourage and facilitate drug development for products designed to treat rare diseases, also provides substantial potential benefits to the sponsor, including funding for certain clinical studies, study-design assistance, tax incentives and seven years of market exclusivity for the product upon regulatory approval.
Athersys is working in collaboration with leading independent experts and certain partners to evaluate the potential for MultiStem in a range of disease areas, including treatment of various conditions involving immune system dysfunction, as well as for treating cardiovascular disease and certain neurological conditions. In multiple preclinical models, administration of MultiStem has been shown to be non-immunogenic, even when administered without tissue matching or immune suppression, and appears to promote healing and tissue repair through multiple biological mechanisms. Results from various studies demonstrate that MultiStem has potent immunomodulatory properties that the Company and its collaborators believe could have relevance toward the treatment of various inflammatory and autoimmune disease conditions such as Inflammatory Bowel Disease (IBD). In December 2009, Athersys announced a partnership with Pfizer focused on the development of MultiStem for IBD, and in November 2010, the companies announced that they had received FDA authorization to conduct a double blind, placebo controlled Phase II clinical trial in patients with moderate to severe ulcerative colitis.
Date: January 6, 2010
Source: Athersys, Inc.

Esperion Begins ETC-1002 Trial

Esperion Begins ETC-1002 Trial
Drug Discovery & Development - January 06, 2011

Esperion Therapeutics, a privately held biotechnology company working to discover, develop and commercialize treatments for cardiovascular and metabolic diseases, announced that it has initiated a Phase 2 clinical study for ETC-1002, the company’s lead product candidate. ETC-1002 is a novel small molecule compound that has demonstrated preclinical and clinical activity as a metabolic regulator of imbalances in lipid and carbohydrate metabolism. The compound acts to inhibit fatty acid and cholesterol synthesis and enhance fatty acid oxidation. ETC-1002 has the potential to regulate LDL-C, HDL-C, triglycerides, glucose/insulin and other cardio-metabolic risk factors.
The 12-week, multi-site, randomized, double-blind, placebo controlled study will enroll 176 patients with hypercholesterolemia, with or without high triglycerides, to assess the role of ETC-1002 in lipid regulation (LDL-C and triglycerides). This Phase 2 trial builds on positive data from the Phase 1 program in which ETC-1002 demonstrated a statistically significant lowering of LDL-C in mildly dyslipidemic subjects and a favorable safety profile in both single and multiple-dose studies in more than 70 patients. A second Phase 2 clinical study is planned in 2011 to validate other attributes observed in preclinical studies with ETC-1002 which further support its pharmacological effects as a metabolic regulator.
"Cardio-metabolic diseases remain the leading cause of morbidity and mortality among men and women in industrialized countries worldwide," said Roger Newton, PhD, President and CEO of Esperion. "Our preclinical research has shown ETC-1002 regulates lipids, atherosclerosis, inflammation and glucose/insulin. These data, along with the accumulating clinical evidence, suggest that ETC-1002 may be an effective therapy to regulate metabolic imbalances in lipid and carbohydrate metabolism and could play a significant role in the treatment of patients with symptoms characterized by metabolic syndrome. The efforts to advance ETC-1002 complement Esperion’s other research and development program, focused on optimizing an HDL therapy in a strategic partnership with the Cleveland Clinic.”
Date: January 6, 2010
Source: Esperion Therapeutics