Enzi, Kennedy release final version of drug safety bill
By D. Michele Duarte, Managing Editor
WASHINGTON — Sen. Mike Enzi (R-WY), chair of the Senate Health, Education, Labor, and Pensions (HELP) Committee, and top-ranking Democratic HELP committee member Sen. Edward Kennedy (D-MA) Aug. 3 introduced their final version of the bill — The Enhancing Drug Safety and Innovation Act of 2006 — which would give FDA better authoritative capacity, and more resources to monitor and manage drug safety after drugs are approved.
In a press statement, the senators said they proposed the legislation “in hopes of restoring public confidence in FDA’s review process to weigh the benefits and risks of prescription drugs.”
The Assn of Clinical Research Organizations (ACRO) consecutively issued a press statement welcoming the introduction of S. 3807. “ACRO applauds the leadership of …HELP, on this important piece of legislation aimed at improving the safety of approved drugs while still providing opportunities for the development of the innovative biomedical products that patients need.
“Representing leading clinical research organizations that have great expertise in the conduct of clinical trials, ACRO provided the HELP Committee with information about the research environment…We are pleased that the bill recognizes the need to improve the science of clinical trials and the long and costly process of developing new biomedical products.”
The legislation creates an institute to identify new tools for progressing biomedical research and develop programs and award grants to carry out research priorities. Furthermore, the Enzi-Kennedy legislation contains four titles: Drug Safety; Establishment of the Reagan-Udall Institute for Applied Biomedical Research; Clinical Trials Registry and Results Databases; and Reform of Conflicts-of-Interests on FDA Advisory Committees.
Drug Safety
Under the drug safety provision — Title I of the Enhancing Drug Safety and Innovation Act — if the agency believes a labeling change is necessary, it can request that the product sponsor make the change. If the product sponsor does not agree to the change, the agency cannot order the labeling change. FDA also may initiate a misbranding action in the courts.
Moreover, under the bill, drugmakers would be required to work with FDA to develop risk evaluation and mitigation strategies (REMS) before a drug is approved that would help firms and regulators better assess post-marketing adverse-event (AE) reports and more efficiently communicate risk information to the public after a drug is approved.
Under REMS, pharmaceutical firms also may be required to conduct post-marketing trials, also known as Phase IV studies. REMS also may require drug companies to develop medication guides for distribution when a drug is dispensed, patient package inserts and plans for disseminating risk information to health care providers.
Furthermore, the bill requires drug companies to submit REMS assessments to FDA on an annual basis for the first three years after a medication is approved. Regulators may increase or reduce the frequency of assessment submissions after the drug has been marketed for three years. The legislation also allows FDA to discontinue the requirement for annual REMS assessments after three years if the agency determines that serious risks have been adequately identified, assessed and managed.
Additionally, under REMS, pharmaceutical firms may be required to submit drug advertisements to FDA for preclearance to ensure that risks are clearly communicated to health care providers and the public. This measure would include disclosure of certain information in advertisements, such as, a statement acknowledging that all serious risks associated with the drug’s use may not have been fully identified or assessed at the time the medication was approved.
Lastly, REMS may also require a drug firm to restrict the distribution of a product; and the legislation would require companies that violate REMS agreements to be fined $15,000 to $250,000 per violation — not to exceed $1 million — for all violations adjudicated in a single proceeding.
Dispute resolution would be conducted via a process that “brings fairness, timeliness and finality to the response to new safety information.” For example, once FDA/sponsor discussions of a sponsor’s proposed REMS begin, the sponsor may request review by the Drug Safety Oversight Board (DSOB) from day 20 until day 45; both the sponsor’s proposed REMS and FDA’s alternative would then go to the next meeting of DSOB for review; DSOB would then review both proposals and make recommendations to the HHS secretary within five days.
Establishment of the Reagan-Udall Institute for Applied Biomedical Research
Title II of the Enhancing Drug Safety and Innovation Act would ensure that a public-private partnership, known as the Reagan-Udall Institute for Applied Biomedical Research, would facilitate improvements in drug and device sciences by coordinating research activities between the regulators at FDA and academic and industry researchers.
Activities of the institute would include, but would not be limited to, identifying and pursuing research priorities to aid in the modernization of medical product development and enhancement of product safety so that research findings are quickly incorporated into regulatory regimes; coordinating and expanding existing government research and development programs and award grants; and, establishing collaborations to carry out research priorities.
The institute would be supported initially by federal funds, and then by a combination of federal funds and contributions from the pharmaceutical and device industries and philanthropic organizations.
Clinical Trials Registry and Results Databases
The Clinical Trials Registry and Clinical Trials Results Database would be critical parts of the drug safety processes. Title III of the Enhancing Drug Safety and Innovation Act would establish a publicly available database at NIH to help enhance patient enrollment in clinical trials of drugs for any disease or condition and provide a mechanism to track subsequent progress of trials. This database would replace ClinicalTrials.gov, which would cease operations but remain publicly accessible.
Moreover, late Phase II, Phase III and Phase IV clinical trials would be required to register with the database. Basic, searchable pieces of information about the trial would be required to be placed in fields in the database entry, while the bulk of the information about the trial would be in a narrative summary document. The information would then be submitted after a trial is cleared by the Institutional Review Board but before patients enroll.
Title III also would establish a publicly available database to ensure that results of trials are made public, and that patients and providers have the most up-to-date information. Like the registry, certain basic pieces of information would be placed in searchable fields in the database, while the bulk of the information would be in two summary documents (lay and technical). Both summary documents would be publicly available.
Medical journals also would be able to query the database to determine whether results had been submitted, since many journals require submission of results to a database for publication; and o Failure to submit required information, or the submission of false, misleading or promotional information would be a prohibited act under the Federal Food, Drug and Cosmetic Act.
Lastly, state clinical trial databases would be preempted, and compliance with data submission requirements could not be used as evidence of off-label promotion of the drug.
Reform of Conflicts-of-Interests on FDA Advisory Committees
Title IV of the Enhancing Drug Safety and Innovation Act would make improvements to FDA’s process for screening advisory committee members for financial conflicts-of-interest. Recently, there have been questions raised about conflicts-of-interest that panel members on FDA Advisory Committees may have because of industry funding or other financial interests.
Under this new provision, new candidates for appointment to advisory panels would be screened by FDA with the goal of minimizing potential conflicts-of-interest; FDA would be directed to enhance public nomination of individuals for service on advisory committees in order to expand the pool of qualified candidates; FDA would be directed to define how interests imputed to an individual (such as, financial interests of an employer) bear on eligibility for service on an advisory committee; and all financial involvements of panel members at a meeting would be required to be read into the public record of advisory committee meetings.
Moreover, Office of Inspector General would be directed to periodically review the current activities of past advisory committee members to ensure that individuals are not rewarded for their past votes as members of an advisory committee.
If enacted, the Enhancing Drug Safety and Innovation Act of 2006, S. 3807, would “raise the bar to ensure that drug safety is not an afterthought, but an integral part of the process from the very beginning,” Enzi concluded.
“It requires drug makers to engage in better safety planning before a drug is approved for release to the public, and will improve both the understanding of and response to risks that arise after a drug is on the market.
A bulleted summary of the final draft of The Enhancing Drug Safety and Innovation Act of 2006 can be downloaded at http://help.senate.gov/S___Bill%20Summary.pdf. The Enzi-Kennedy press release can be accessed at http://help.senate.gov/Maj_press/2006_08_03_a.pdf.
Depositions indicate Bush Administration exerted political influence on FDA during Plan B review process; Plan B decision made before data review
By D. Michele Duarte, Managing Editor
WASHINGTON — Depositions released Aug. 3 by the Center for Reproductive Rights in its lawsuit against FDA indicate that the Bush Administration sought to influence the agency during the Plan B, over-the-counter (OTC) status, application review process.
One senior FDA scientist, Florence Houn, M.D., testified in July that she was told by Janet Woodcock, M.D., then acting deputy commissioner of FDA, of the need to appease the “administration’s constituents” by “rejecting over-the-counter (OTC) status for women of all ages and then approving it down the road with an age restriction.” This testimony directly contradicted the testimony of Woodcock, who earlier testified that she was not aware of any political pressure.
The Center for Reproductive Rights’ request to subpoena the White House, discussed at a hearing at U.S. District Court for the Eastern District of New York was, in part, based upon the revelations disclosed in the depositions of Mark McClellan, M.D., and Houn.
The center Aug. 3 also released the depositions of two FDA scientists, Curtis Rosebraugh, M.D., and Donna Griebel, M.D., who testified to “the unusual involvement from senior FDA management at the earliest stages of the Plan B review process.”
Moreover, based on testimony given in June by former FDA Commissioner McClellan, who now serves as administrator for the Centers for Medicare and Medicaid, the Center for Reproductive Rights said it also is seeking to depose Jay Lefkowitz, a former White House domestic policy advisor, regarding conversations he had with McClellan during FDA’s review process of Plan B.
Adding to the potential conflict-of-interest issue, FDA officials also said in the court documents, released Aug. 3, that the decision whether FDA should approve wider access to a morning-after contraceptive drug was made well before agency scientists finished their final review.
In a sworn statement in June, John Jenkins, M.D., director of FDA’s Office of New Drugs, said he learned in early 2004 that then-FDA Commissioner Mark McClellan had decided against approval before the staff could complete their analysis.
McClellan, who led FDA when Barr Pharmaceuticals, Woodcliff Lake, NJ, submitted its application in 2003, said he gave updates to the White House as a matter of course but denied they told him what to do. “If I was being given any direction on how I should act on this application, I would have remembered that because that never happened,” McClellan insisted in a sworn statement.
The court depositions were released just two days after the agency had promised to reopen discussions with Barr on the OTC issue. The prolonged delay by FDA, and then FDA’s abrupt announcement to reopen discussions, had already stirred debate over politics and science and held up the confirmation of two agency chiefs. [See Bioresearch Compliance Report online, Aug. 2]
FDA reiterated to the press Aug. 7 that the initial rejection of Plan B was based on the lack of data over whether younger girls could use the product safely. But, other FDA officials have consistently said that they were left out of the decision to postpone a ruling and that FDA was holding up its decision to appease the Bush Administration.
Conversely, although FDA said it plans to meet with Barr on Aug. 8, FDA spokesperson Susan Bro declined to comment on the suit. “What matters is where we are today [on Plan B],” she said.
The lawsuit Tummino v. von Eschenbach was filed on Jan. 21, 2005, by the Center for Reproductive Rights in the U.S. District Court for the Eastern District of New York on behalf of the Assn of Reproductive Health Professionals, the National Latina Institute for Reproductive Health, and individuals from a grassroots advocacy group, the Morning-After Pill Conspiracy.
Full texts of the depositions released Aug. 3 can be found at the Center for Reproductive Rights website at http://www.reproductiverights.org/pr_06_0803FDADepositions.html.
Gene research/genomics
St. Jude researchers determine why gene therapy treatment caused leukemia in some severe immune deficiency patients
Scientists at St. Jude Children’s Research Hospital Aug. 1 said it has developed a mouse model of a severe disease of the immune system that helps explain why gene therapy used to treat children with “Bubble Boy” disease at an institution in Europe caused some of them to develop leukemia.
The disease, called X-linked severe combined immunodeficiency (XSCID), is caused by a mutation in a gene called gamma C that prevents the immune system from forming B and T lymphocytes.
In gene therapy for this disease, normal copies of the gamma C gene are inserted into stem cells that later give rise to these lymphocytes. Following the development of leukemia by the patients in France, researchers determined that some of the gamma C genes had inserted themselves into oncogenes-cancer causing genes. This caused the stem cells to multiply uncontrollably and produce leukemia.
The St. Jude researchers concluded that XSCID itself makes their mouse models-and by extension, children with this disease particularly susceptible to cancer caused by gene therapy. Specifically, the team found that the population of primitive stem cells that is the target of gene therapy is abnormally large. This increases the chance that gamma C genes that are put into the cells will insert themselves into oncogenes-genes that cause cancer when activated.
“One major implication of this finding is that gene therapy for other forms of genetic blood diseases will pose significantly less risk for causing cancer than was previously thought,” said Brian Sorrentino, M.D., director of the St. Jude Experimental Hematology Division and co-director of Transplantation and Gene Therapy.
Sorrentino also is the senior author of a report, which appears in the Aug. 1 issue of “Proceedings of the National Academy of Sciences.”
“Our current findings with this new mouse model offer real hope that we can make gene therapy for X-linked SCID safe as well as effective,” added Yan Shou, Ph.D., the first author of the paper and the major contributor to the work.
Third gene linked to higher breast cancer risk
Scientists at the University of Copenhagen and Herlev University Hospital in Denmark, said they have found a third gene mutation linked to high rates of breast cancer. According to the researchers, it is the CHEK2 mutation, although not as important as the BRCA1 and BRCA2 mutations in indicating breast cancer risk.
In the study, 0.5% of the 9,231 Danish women had the mutation and 12% of them developed breast cancer, compared to 5% of the women who did not carry the mutation.
Additionally, the authors noted that women who had the mutation were generally over 60, overweight and taking hormone-replacement therapy. According to the study, which will be published upcoming issue of the “Journal of Clinical Oncology,” these high-risk women had a 24% chance of developing breast cancer in 10 years.
Penn. researchers determine structure of smallpox virus protein bound to DNA
Researchers at the University of Pennsylvania School of Medicine said they have determined the structure of an important smallpox virus enzyme and how it binds to DNA.
The enzyme, called a topoisomerase, is an important drug target for coming up with new ways to fight smallpox, they emphasized.
DNA-modifying enzymes bind to specific sequences in the genetic code to aid in the many steps of DNA replication.
The smallpox virus is one of the most easily transmissible infectious diseases known to humans, resulting in up to 30% mortality. The efficiency with which it spreads, combined with the deadly nature of the disease, has raised fears that smallpox could be revived for use in bioterrorism.
Knowing the exact three-dimensional structure of smallpox virus proteins could help researchers design antiviral agents. Poxviruses are large viruses that contain two strands of DNA and replicate themselves entirely in the cytoplasm of infected cells. Poxviruses do not take over the genetic machinery inside the nucleus of the host cell, as many viruses do. Because of this strategy, poxviruses encode many of the enzymes they need to replicate their own genes, and hence reproduce.
One of these enzymes, the authors explained in their article — published in the Aug. 4 issue of “Molecular Cell” — is a topoisomerase, which is used by the virus to relieve the excessive twisting of DNA strands that normally occurs during DNA replication and transcription of the viral genes. Upon initial infection, the poxviruses come already equipped with some proteins, including topoisomerases, to kick-start replication.
“This enzyme is one of the most closely studied DNA-modifying enzymes in biology,” said Frederic Bushman, PhD, professor of microbiology, and one of the senior authors. “The structure of the DNA complex has been long-awaited.”
Sticky DNA helps spot leukemia
U.S. researchers have developed a new technique to distinguish leukemia cells from healthy ones.
According to a report by BBC, a University of Florida team has developed a set of DNA probes, which only stick to cancer cells, making it easier to identify them.
Using this knowledge, the Florida team designed hundreds of DNA probes labeled with a fluorescent protein. Following tests, they were able to identify those probes that stuck only to proteins found on the surface of cancer cells.
The sticky DNA allowed the researchers to readily identify the “labeled” cancer cells using a cell-sorting machine more accurately than could be done by the human eye using a microscope.
Researchers find on-off “switch” for muscular dystrophy
Researchers at the University of Florida said they have been able to reverse muscular dystrophy (MD) in mice using a therapy that could eventually be used in humans.
The key, they explained, was silencing toxic messenger RNA molecules, which are created by faulty DNA code, that create abnormalities which in turn causes a progressive weakening of muscles, wasting and heart ailments.
Weakening of muscles, wasting and heart ailments are all common symptoms of myotonic dystrophy, the most common form of MD.
The researchers first developed mice with faulty DNA that could be turned “on” or “off” by adding or eliminating an antibiotic in their water supply. In the “off” phase normal muscle activity returned in many of the mice.
“The results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules,” the researchers emphasized. “
The fact that the course of the disease can be reversed both overtly and at the molecular level suggests that the toxic RNA functions as a reversible metabolic toxin.”
The work, to be published this week in the “Proceedings of the National Academy of Sciences,” builds on previous research at UF and the University of Rochester School of Medicine and Dentistry that revealed myotonic dystrophy is caused by malfunctioning genes that block the action of key proteins in cells, including one known as the muscleblind protein. These proteins, which help muscle and eye cells mature, stick to warped copies of RNA molecules that build up in a cell’s nucleus and prevent the proteins from working properly.
“A means of delivering the treatment to humans still needs to be developed, but this now provides proof of principle that the approach is effective in this important mouse model,” said John Day, M.D., Ph.D., a professor of neurology at the University of Minnesota School of Medicine.
“For the first time this really raises the hope of people suffering from this common form of MD that a treatment could someday be forthcoming that will address the many serious components of this disease.”
Scientists uncover key event in apoptosis
Researchers at St. Jude Children’s Research Hospital said they photographed cells in their death throes and found apoptosis, or “cell suicide,” occurs as a rapid, single event rather than a sequential process as previously believed.
The researchers also found the rapid formation of pores in the mitochondrial membranes allows the nearly simultaneous release of many apoptosis proteins.
Essentially, results of the study, which appear in the “Proceedings of the National Academy of Sciences,” indicated the formation of pores in the mitochondrial membranes is a rapid process that allows a nearly simultaneous, rather than a sequential, release of many apoptosis proteins.
NIH researchers find RegeneRx’s drug candidate regulates key proteins important in wound repair
RegeneRx Biopharmaceuticals reported Aug. 1 that researchers at NIH found that its TB4 (Thymosin Beta 4), administered to wounds in laboratory animals, significantly increased several important wound healing proteins called matrix metalloproteinases (MMPs), including MMP-2 and MMP-9.
The researchers surmised that it is likely that other proteinases may also be regulated (up or down) by TB4.
Matrix metalloproteinases are important for normal wound healing. These proteins clean wound debris, stimulate cell migration to the wound site, and help remodel collagen fibers to complete the healing process. It is also known that the level and type of proteinases are very important in wound repair. MMP-2 and MMP-9, two of over 25 identified MMPs, are specifically found in fibroblasts and keratinocytes, two cell types intimately involved in the would healing process.
Thus, according to Hynda Kleinman, M.D., in whose laboratory the research was performed, “these data demonstrate an additional mechanism by which TB4 may promote wound repair. This protein [TB4] may thus accelerate repair by multiple, related, and in some cases, interdependent mechanisms involving cell migration, angiogenesis, inflammatory response and protease production and activity.”
TB4 is a synthetic version of a naturally occurring peptide present in virtually all human cells. It is a first-in-class drug candidate that promotes endothelial cell differentiation, angiogenesis in dermal tissues, keratinocyte migration, collagen deposition; and, it down-regulates inflammation.
One of TB4’s key mechanisms of action is its ability to regulate the cell-building protein, actin, a vital component of cell structure and movement. Additionally, TB4 directly influences the production of laminin-5, a protein responsible for proper adhesion and migration of certain types of mammalian cells and often deficient in patients with patients with epidermolysis bullosa (EB) — a genetically transmitted disorder characterized by marked fragility of the skin.
TB4 also has recently been reported to inhibit or prevent apoptosis in ocular tissue and cardiac tissue.
The findings are published in the “Journal of Cellular Physiology.”
Stem cell/cell research
Ortec’s FDA-approved cell line plays pivotal role in creation of first embryonic stem cell lines fit for human clinical trials
Ortec International, New York, Aug. 3 announced that their collaboration with ES Cell International (ESI), Singapore, in connection with the development of ESI’s human embryonic stem cell (hESC) derived cell therapy products, has yielded its first significant milestone.
According to Ortec, ESI has produced and stored what it believes to be the first clinically compliant human embryonic stem cell lines. These cell lines were derived using feeder cells from viral-tested human cells rather than mouse cells, and, therefore, should be able to be used in human clinical trials to develop novel stem-cell therapies.
The feeder cells used by ESI in developing these cell lines were manufactured by Ortec and are FDA-approved and manufactured under current GMPs regulations.
Calif. stem-cell board to call for research proposals; $150-million loan will fund first grants
Armed with the $150-million loan it just received from Gov. Arnold Schwarzenegger, the board overseeing California’s $3-billion stem-cell institute said Aug. 3 it will begin soliciting its first research proposals within weeks, the “Mercury News” reported. [See Research Compliance Report online, July 24]
The board also approved a policy to guard against bias in awarding grants by requiring the institute’s advisory boards to disclose ties to companies or universities doing stem-cell work.
The board plans to award 70 grants totaling $151.5 million, all of it allocated for studying human embryonic stem cells, which are derived from embryos and can grow into any type of tissue.
The institute was created by California voters in 2004 primarily to conduct that kind of research, after President Bush limited federal financing in that area. But lawsuits have held up the institute’s $3 billion funding for more than a year.
The issue of imposing conflict-of-interest rules on the board’s advisers has been controversial. Consumer advocates say the advisers should not have ties to those seeking the institute’s grants to ensure that the agency’s decisions are unbiased. But, some institute officials have been reluctant to impose such limitations, fearing the advisers might be discouraged from helping the agency.
Under the rules adopted Aug. 2, the experts must disclose their investments and avoid offering recommendations about businesses, universities or others with which they have a financial, personal or professional relationship.
Atomic force microscopy finds application in neuroscience
To understand how brain cells release compounds (or transmitters) used when the cells communicate with each other, Vladimir Parpura, associate professor of neuroscience, and Umar Mohideen, professor of physics, from the University of California–Riverside, devised a new technique, used commonly in physics, which can now be applied to the study of a wide range of biological processes and interactions.
The researchers, who performed their experiments on brain proteins called SNAREs, published the results in “Biophysical Journal.”
The technique, commonly referred to as Atomic Force Microscopy, uses the deflection of microfabricated membranes of silicon nitride, about 100 times thinner than the human hair, to measure very small forces. Using this technique on rat brain proteins, the researchers were able to measure the bonding between single protein molecules that are involved in the release of the neurotransmitters. They also were able to classify the strength of the molecular interactions (bonding) between three of the SNARE proteins that participate in the process.
SNARE proteins are located on vesicles and the plasma membrane of brain cells. These proteins are thought to play a key role in the final fusion of the synaptic vesicle with the plasma membrane, a process that makes communication between cells possible.
“Our results shed new light on how these proteins are involved in exocytosis — the process by which a biological cell releases substances into its environment,” Parpura said.
“We now understand better how these proteins interact at the molecular level and we can apply this to improve our detection of toxins acting on these proteins.”
Research and development
NCI scientists develop new model for estimating risk of melanoma
A team of researchers, led by scientists at National Cancer Institute (NCI) has developed a model for estimating the five-year risk of melanoma, a potentially deadly skin cancer.
This model, a first iteration that is subject to further refinement, can be used by health professionals to identify individuals at increased risk of melanoma and help them plan for potential interventions, according to the report, which appears in the “Journal of Clinical Oncology.”
Specifically, the researchers’ model identifies high-risk individuals based on information that healthcare providers can obtain easily during a routine office visit and does not require the patient to fully disrobe. This gender-specific model uses information on skin complexion and sun exposure, and a physical examination of the back and shoulders to estimate the probability of an individual developing a first primary melanoma over the next five years.
The model is designed for physicians to assess non-Hispanic white men and women between 20 and 70 years of age. If, after using the calculator, a health professional finds a person to be at high risk for melanoma, the researchers suggest that the individual undergo interventions, including a complete skin examination, counseling to avoid sun exposures, regular self- and professional surveillance, or participation in prevention trials.
The model is not intended to assess the risk of individuals with a prior melanoma or non-melanoma skin cancer or for those with a family history of melanoma, as they are already recognized as being at high risk.
In order to build a model for predicting melanoma risk, scientists surveyed 718 non-Hispanic, white patients with invasive melanoma from melanoma clinics. The researchers matched these cases with 945 patients without disease.
The participant survey included questions about the number of sunburns and suntans, and family history of melanoma, along with medical, occupational, residential and outdoor exposure histories. Each participant also had a complete skin examination, during which freckling pattern, skin color, sun damage and counts of small moles (greater than or equal to 2 millimeters in size and less than 5 millimeters in size), large moles (greater than or equal to 5 millimeters in size), and dysplastic nevi (moles that are considered to be precancerous or more likely to turn into melanoma) were recorded.
From these data, certain elements were selected to define the risk of melanoma in men and women separately, and risk models were developed similar to those developed using the Gail model for breast cancer risk. Also incorporated into the melanoma model were U.S. rates of new cases and deaths from melanoma for 1992-2001 in different geographic areas. The combination of selected elements yielded an attributable risk (the proportion of melanoma diagnoses attributed to the study variables) of 86% for men and 89% for women, using at most seven elements.
Attributable risks did not vary by age, ultraviolet B exposure, or hours spent outdoors. The observed individual risks varied widely, depending on age, other host characteristics, and geographic area. Ultimately, these observed risks led the scientists to develop a tool for calculating the absolute risk for an individual. The tool is available at http://dceg.cancer.gov/melanomarisktool.
Osteoarthritis Initiative releases first data
The Osteoarthritis Initiative (OAI), a public-private partnership between NIH and private industry that seeks to improve diagnosis and monitoring of osteoarthritis (OA) and foster development of new treatments, has released its first set of data Aug. 2.
Researchers can now analyze the data to form new hypotheses for further study of OA, which is the major cause of activity limitation and disability in older people. Images, including x rays and magnetic resonance imaging scans, will also be available to researchers upon request. All data are stored with an anonymous identification number to protect the confidentiality of the participants’ information.
Over the next five years, the OAI said it plans to provide an unparalleled, state-of-the-art longitudinal database of images and clinical outcome information to facilitate the discovery of biomarkers for development and progression of OA. In this case, a biomarker would be a physical sign or biological substance that indicates changes in bone or cartilage.
Data gathered from participants is available to researchers at http://www.oai.ucsf.edu. The data include symptoms; pain severity; a measure of pain, stiffness, and function known as the WOMAC OA index; walking ability; endurance; balance and strength; nutrition; and prescription medicines and alternative therapies used by the participants.
A second set of data will be released later in 2006, and a third release will take place early in 2007. Subsequent data will be released at approximately six-month intervals.
Siga gets NIH grant for smallpox drug development
Siga Technologies, New York, announced Aug. 4 it has received a $4.8-million grant from NIH to support the ongoing development of the company’s lead smallpox drug candidate, SIG A-246.
Recently SIGA-246 successfully completed its initial human safety clinical trial.
According to the company, smallpox is very easily transmitted from person to person, and is associated with mortality rates of 30-60% with 90% morbidity.
Mass immunizations of the general population using the current live vaccine are not recommended, as there are known complications in certain individuals from vaccination. At present, there is no approved treatment for smallpox that can be safely administered to the general population without significant risk of AEs.
People
Gene Logic restructures Genomics division; eliminating approximately 80 positions
Gene Logic, Gaithersburg, MD, Aug. 1 announced it has initiated a plan to reduce the number of employees in its genomics division and related corporate staff by eliminating approximately 80 positions, effective Oct. 5.
The action is being taken as part of an ongoing strategic review of the genomics business, the company said.
Affected employees will be given severance and outplacement assistance costing approximately $1.5 million.
Retained employees will support existing products and services and ensure ongoing service levels are effectively maintained for current and prospective customers. Staff in the company’s preclinical and drug-repositioning divisions will not be affected by this reduction.
Once fully implemented, Gene Logic said it estimates that these staff reductions will reduce its annual salary and fringe benefits costs by approximately $8.0 million.
Semafore adds former Eli Lilly oncology R&D leader to its SAB
Semafore Pharmaceuticals, Indianapolis, Aug. 1 announced that Homer Pearce, M.D., has joined the company’s scientific advisory board (SAB).
Pearce recently retired from Lilly Research Labs, where he served as a member of the executive leadership in discovery research. At Lilly, Pearce also served as VP of cancer research and clinical investigation.
Throughout his career, Pearce was involved in the development of more than 25 INDs that entered clinical trials for cancer, of which three have resulted in regulatory approvals and others are still in development. These drugs include Lilly’s Gemzar (gemcitabine) and Alimta (pemetrexed), which achieved 2005 combined worldwide sales of nearly $2-billion dollars; and the molecular targeted therapeutic, enzastaurin, which is now in Phase III clinical trials.
“We are honored to have such a distinguished cancer drug developer with the breadth of Dr. Pearce’s experience joining our SAB,” said Joseph Garlich, M.D., president and chief scientist, Semafore.
“Dr. Pearce’s extensive knowledge of cancer drug development could not come at a better time as Semafore moves into clinical trials with our lead cancer drug SF1126 and brings our other PI3K inhibitor and PTEN programs forward.”
Pearce currently serves as a business director or scientific advisor to a number of leading research institutions, foundations and biotechnology companies.
Trial news updates
Allos Therapeutics, Westminster, CO, Aug. 2 announced that it has reached agreement with FDA under the Special Protocol Assessment process on the design of a pivotal Phase II trial of the company’s novel, next-generation, antifolate PDX (pralatrexate) in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The Phase II, non-randomized, open-label trial will look to establish the safety and efficacy of PDX with concurrent vitamin B12 and folic acid supplementation in patients with relapsed or refractory PTCL. Patients will receive PDX at 30 mg/m2 once every week for six weeks followed by one week of rest per cycle of treatment. The company currently plans to enroll 100 evaluable patients at approximately 35 leading cancer centers in the U.S., Canada and Europe. The study protocol also includes interim assessments of safety and response. Interim results from a Phase I/II study of PDX in patients with relapsed or refractory non-Hodgkin’s lymphoma and Hodgkin’s disease, which is currently on-going at Memorial Sloan-Kettering Cancer Center, demonstrated preliminary evidence of activity in patients with various subtypes of aggressive and chemotherapy resistant T-cell lymphoma. As reported at the 2005 American Society of Hematology annual meeting, four of seven evaluable patients with T-cell lymphoma achieved a complete response following treatment with PDX, despite having failed multiple prior therapies. The addition of vitamins to the treatment regimen appeared to successfully mitigate the previously established, dose-limiting toxicity of stomatitis. PDX is a small molecule chemotherapeutic agent that inhibits dihydrofolate reductase (DHFR) — a folate-dependent enzyme involved in the building of DNA and other processes. PDX was rationally designed for improved transport into tumor cells via the reduced folate carrier, and greater intracellular drug retention. These biochemical features, together with preclinical data in a variety of tumors, suggest that PDX has an enhanced potency and toxicity profile relative to methotrexate and other related DHFR inhibitors.
Columbia Labs, Livingston, NJ, Aug. 1 announced it has completed enrollment in its randomized, double-blind, placebo-controlled Phase III study of Prochieve 8% (progesterone gel) for a new indication, the prevention of preterm birth. This large-scale global trial involves over 600 patients at more than 60 centers throughout the U.S., Europe, South America, Asia and South Africa. It is designed to assess the ability of Prochieve 8% to safely, effectively and tolerably prevent preterm birth in pregnant women who are predisposed to this problem. Prochieve 8% is currently FDA-approved and commercially available to treat infertility and secondary amenorrhea. Prochieve 8% is a bioadhesive product that utilizes Columbia Laboratories’ proprietary bioadhesive delivery system to deliver natural progesterone vaginally in a convenient and easy-to-use, pre-filled, tampon-like applicator. By using a non-immunogenic (hypoallergenic) bioadhesive polymer designed to adhere to the vaginal tissue, Prochieve 8% promotes controlled and sustained absorption of progesterone and minimizes leakage, a side effect commonly seen with vaginal suppositories. As a result, the product does not restrict normal activities. Prochieve 8% contains 90 mg of natural progesterone. It is FDA-approved for progesterone supplementation or replacement as part of an assisted reproductive technology treatment for infertile women with progesterone deficiency and for the treatment of secondary amenorrhea, and is safe for use during pregnancy.
Exelixis, South San Francisco, Aug. 1 announced the initiation of a Phase II trial of XL647, an orally bioavailable small molecule inhibitor of the HER2 [a proto-oncogene located at the long arm of human chromosome 17]; EGF [epidermal growth factor]; VEGF [vascular endothelial growth factor]; and EphB4 [a type of epherin protein, which is highly produced in malignant human breast tumors] receptor tyrosine kinases (RTKs). Although these individual RTKs are targets for currently approved therapies, XL647 was designed to potently inhibit all targets simultaneously. The trial will be conducted in patients with advanced (stage IIIB or IV) non-small cell lung cancer (NSCLC) who have not previously been treated with chemotherapy. In this proof-of-concept trial, participants must meet at least two of the following criteria: (1) be of the Asian race, (2) be of the female gender, (3) be a non-smoker, or (4) have adenocarcinoma. The multi-center, open-label Phase II study will be conducted in up to 15 clinical sites and will follow a two-stage enrollment strategy. The primary objectives of the Phase II study are to determine the response rate of subjects with NSCLC treated with XL647 and to evaluate the safety and tolerability of XL647. Secondary objectives include assessment of progression-free survival, duration of response, and overall survival, and characterization of pharmacokinetic and pharmacodynamic parameters of XL647. At the June 2006 annual meeting of the American Society of Clinical Oncology, researchers presented dated showing that XL647 exhibited favorable safety and tolerability profiles in a Phase I trial in patients with advanced solid tumors. The investigators reported that of 40 evaluable patients, one NSCLC patient had a partial response; and, 12 other NSCLC patients, three chordoma patients, two adenoid cystic carcinoma patients, an adrenocortical carcinoma patient, a colorectal patient, an ovarian cancer patient, an mesothelioma patient, and a head and neck cancer patient have had prolonged stable disease (>3.5 months). XL647 is a potent inhibitor of multiple RTKs implicated in driving tumor cell proliferation and tumor vascularization. XL647 inhibits the EGF, HER2, and VEGF RTKs, each of which is a target of currently approved cancer therapies.
GPC Biotech AG, Munich, Germany, Aug. 2 announced the initiation of a Phase II randomized trial evaluating the company’s lead drug candidate, satraplatin, in combination with OSI Pharmaceuticals’s, Melville, NY, Tarceva (erlotinib) as a first-line therapy in patients with inoperable advanced NSCLC who are 70 years of age and older. A Phase III registrational trial exploring satraplatin in combination with prednisone as a second-line chemotherapy treatment for patients with hormone-refractory prostate cancer has completed patient enrollment. GPC Biotech said it is continuing to open additional clinical studies to explore the potential of satraplatin in a variety of tumor types. The Phase II study in advanced NSCLC is a randomized trial that is expected to involve over 20 centers in the U.S. and Europe and enroll approximately 120 patients. The primary objective of this study is to evaluate progression-free survival. The study will also examine overall survival, response rates and safety. Patients in the Phase II trial will be randomized to receive satraplatin plus Tarceva or Tarceva alone. A sequential dosing regimen will be used in the satraplatin arm. The treatment cycle for both arms is 28 days. Patients will be stratified according to smoking history and gender. Satraplatin, an IND, is a member of the platinum family of compounds. Over the past two decades, platinum-based drugs have become a critical part of modern chemotherapy treatments and are used to treat a wide variety of cancers. Unlike the platinum drugs currently on the market, all of which require intravenous administration, satraplatin is an orally bioavailable compound and is given as capsules that patients can take at home, GPC emphasized.
Hana BioSciences, South San Francisco, Aug. 3, announced the initiation of a Phase I clinical study of Sphingosome Encapsulated Vinorelbine in patients with advanced solid tumors. This Phase I study is designed to assess the safety, tolerability and preliminary efficacy of Sphingosome Encapsulated Vinorelbine in patients with advanced solid tumors. Hana is developing this compound for patients with NSCLC and breast cancer, among others. The study is being conducted at the Cancer Therapy and Research Center, San Antonio, and McGill University, Montreal. Vinorelbine, a semi-synthetic, vinca alkaloid, is a microtubule inhibitor that has been approved for use as a single agent or in combination with cisplatin for the first-line treatment of advanced NSCLC. Vinorelbine also is widely used for the treatment of breast cancer. Sphingosomal encapsulation is a targeted liposomal drug delivery platform, which is designed to significantly increase tumor targeting and duration of exposure for cell cycle-specific anti-cancer agents. Encapsulation also allows an increase in dose intensity without increased toxicity, in preclinical studies. Vincristine, vinorelbine and topotecan are approved cancer therapies that have been selected for sphingosomal formulation specifically for their ability to benefit from this novel encapsulation. According to Hana, the possible advantages of sphingosomal drug delivery include a longer circulation time in plasma, which delivers more of the therapeutic agent to targeted tumor sites over a longer period of time; slow release of the drug from extravasated sphingosomes, which increases drug levels within the tumor, extends drug exposure through multiple cell cycles, and significantly enhances tumor cell killing; and, increased drug concentration at the tumor site, which is believed to be associated with increased clinical activity.
Icagen, Research Triangle Park, NC, Aug. 4, announced that following a planned interim safety, efficacy and futility analysis by an independent Data Monitoring Committee (DMC) of the company’s Phase III trial of ICA-17043 for the treatment of sickle cell disease, the DMC recommended that enrollment continue for patients on concurrent hydroxyurea therapy. Approximately half of the patients enrolled in the study to date are on concurrent hydroxyurea therapy. For currently enrolled patients not on hydroxyurea, the DMC recommended that study drug be discontinued and that patients proceed to the end-of-study, follow-up period. This recommendation by the DMC was made after the analysis of efficacy, safety and futility. The DMC noted further that there were no specific safety issues identified. Finally, the DMC has requested additional data and will reconvene when these are available. The trial will now enroll only patients who are on concurrent hydroxyurea therapy. While patients not on hydroxyurea will discontinue study drug and enter the eight-week follow-up phase. ICA-17043 is a novel, small-molecule ion channel-inhibitor under development for the chronic prophylactic treatment of sickle cell disease. This novel drug candidate is taken orally and is being developed for once-a-day dosing. ICA-17043 has received both Fast Track designation and Orphan Drug designation from FDA. ICA-17043 targets a particular potassium channel, called the Gardos channel.
MAP Pharmaceuticals, Mountain View, CA, Aug. 2 announced the initiation and first patient dosing of a Phase II clinical trial evaluating MAP0010. MAP0010 is a proprietary nebulized formulation of budesonide for the inhalation treatment of asthma in both pediatric and adult populations. According to MAP, this novel approach to therapy is intended to provide the same efficacy as the currently marketed nebulizer product, but with a lower dose delivered in less time. The Phase II clinical trial will assess the efficacy of two doses of MAP0010 and will be conducted at multiple clinical sites in the U.S. as a randomized, double-blind, placebo-controlled study in approximately 225 pediatric and adolescent asthma patients. The primary endpoint for the study will be asthma control as assessed by changes in daily and evening asthma symptoms (coughing, wheezing, breathlessness) compared to placebo, with secondary endpoints that will evaluate changes in pulmonary function. Safety evaluations will be made throughout the duration of the clinical trial period.
Napo Pharmaceuticals, South San Francisco, Calif., Aug. 3 announced that it has received approval from the Drug Controller General of India to start a Phase II trial with crofelemer, Napo’s proprietary gastrointestinal compound for the treatment of acute infectious diarrhea. The trial will be initiated by Glenmark Pharmaceuticals, Mumbai, India. Glenmark is Napo’s product development and commercialization partner for crofelemer in India and more than 110 emerging and developing country economies for the indications of AIDS-related diarrhea, infectious diarrhea and pediatric diarrhea. Upon marketing Glenmark will pay up to 14% royalties to Napo. The trial is expected to commence in calendar 2006 and will involve sixty adult patients suffering from acute diarrhea in a prospective, randomized, parallel group using a controlled double-blind placebo method. The trial will be concluded within three months from the start of dosing. Glenmark is also working on a development plan for the other indications of AIDS-related diarrhea and pediatric diarrhea. Crofelemer is an oligomeric proanthocyanidin and has a well-documented, novel anti-secretory mechanism of action which blocks chloride ion secretion via the CFTR channel [cystic fibrosis transmembrane conductance regulator, which is influenced by chloride movement], normalizes water flow in the gut, treating diarrhea and thereby preventing dehydration from occurring, thus targeting and providing substantial relief for several GI indications. The mechanism of action provides a unique approach for managing diarrhea without the resistance risk of antibiotics. Crofelemer has shown significant anti-diarrheal activities in multiple clinical trials with approximately 1500 patients. Because crofelemer is not absorbed and works locally, it has an important safety advantage over alternative treatments, particularly for chronic administration. Crofelemer is extracted from a medicinal rainforest plant. The drug has now completed Phase II clinical testing for traveler’s diarrhea in an FDA-approved trial and is currently in Phase II clinical testing, sponsored by Napo, for cholera-infected patients in Bangladesh.
NicOx, S.A., Sophia Antipolis, France, Aug. 3, announced that it has successfully completed subject enrolment in the ambulatory blood pressure monitoring (ABPM) trial for naproxcinod (HCT 3012). The randomization of 120 volunteer subjects with stable essential hypertension at 16 clinical centers in the U.S. was initiated in May this year and has been completed ahead of schedule. Results are anticipated in the fourth quarter of 2006. Naproxcinod is a novel, proprietary, first in class COX-inhibiting nitric oxide-donator, which is currently in Phase III clinical development for the treatment of the signs and symptoms of osteoarthritis. At present, non-steroidal anti-inflammatory drugs (NSAIDs) represent the only established symptomatic treatment for the millions of patients who suffer from OA worldwide. However, NicOx emphasized, NSAIDs are known to raise blood pressure and antagonize the blood pressure lowering effect of antihypertensive medications to an extent that may contribute to an increased incidence of cardiovascular events. NicOx said it aims to develop naproxcinod as the drug-of-choice for the treatment of osteoarthritis, especially in those patients with co-existing hypertension, based on nitric oxide’s ability to improve blood pressure control. The ABPM study employs an automatic mobile device to record blood pressure at regular intervals over 24 hours and has enrolled only otherwise healthy, hypertensive subjects. These subjects do not have OA but are between the age of 50 and 75 so as to be representative of the OA population. The trial has a double-blind, randomized, cross-over design, and subjects have been randomized to either one of two groups: approximately 60 are being treated with 750 mg of naproxcinod, twice-daily, for 14-days, followed by 500 mg of naproxen, twice-daily, for 14 days and around a further 60 subjects are receiving the compounds in the opposite order. Blood pressure measurements are being collected using the ABPM device. The primary endpoint of the trial is the mean change from baseline for each active treatment period in the average 24-hour systolic blood pressure recorded during a 24-hour ABPM. A number of secondary endpoints will follow a variety of additional blood pressure parameters, including diastolic blood pressure and blood pressure values recorded during the day and night. The trial will also evaluate the general safety and tolerability of naproxcinod, compared to naproxen.
Response Biomedical, Vancouver, Aug. 3 announced it has begun patient enrollment at four leading sites in the U.S. for the purpose of demonstrating substantial equivalence of the RAMP NT-proBNP Test to a predicate device. The results of this multi-center clinical trial will form the basis for a 510(k) submission and a CE Mark (Conformité Européenne). The four sites conducting the trials are the Mayo Clinic, Minneapolis Medical Research Foundation at Hennepin County Medical Center, Massachusetts General Hospital and San Francisco General Hospital. NT-proBNP (B-type natriuretic peptide) is a biomarker used widely as an aid in the diagnosis of congestive heart failure (CHF). NT-proBNP has also been established as a marker for prognosis in ACS [Acute Coronary Syndrome]. The RAMP NT-proBNP Test has been developed under license from Roche Diagnostics GmbH. NT-proBNP is widely recognized as a definitive cardiac marker for diagnosing CHF. NT-proBNP is cleaved from the precursor peptide proBNP in quantities directly proportional to its biologically active counterpart BNP and in close correlation with the severity of heart failure. BNP [brain natriuretic peptide, a marker of cardiac insufficiency] is secreted primarily from the left ventricle in response to pressure overload and regulates blood pressure, electrolyte balance and fluid volume. BNP acts to reduce the pressure overload. Elevated levels of NT-proBNP indicate the presence of heart failure, and provide physicians with an important diagnostic tool in the early detection and management of CHF. According to Response Biomedical, a study published in the Feb. 17, 2005. issue of the “New England Journal of Medicine,” indicated NT-proBNP also is valuable for risk stratification of patients with stable coronary heart disease and as a prognostic marker across the entire spectrum of cardiovascular diseases. It has the potential to detect early stages of CHF in the absence of clinically obvious symptoms. In addition, it can be used for the assessment of prognosis for patients with CHF and for patients who have previously had a myocardial infarction.
Tanox, Houston, Aug. 3 said it has conducted a meeting with FDA to discuss clinical-trial results and continued development of TNX-355, the company’s antibody being investigated for the treatment of HIV/AIDS. Although FDA indicated that TNX-355 has demonstrated therapeutic potential in clinical testing, an additional dose-finding study will be needed, Tanox said. The company said FDA also indicated that a dose-finding trial, if appropriately designed and successful, could serve as one of the pivotal studies for a BLA submission. Tanox said it expects to continue its discussions with the agency regarding clinical-trial design options over the next several weeks. TNX-355 is a humanized monoclonal antibody and part of the viral-entry inhibitor class of HIV therapies. TNX-355, which is administered intravenously, is distinct from other entry inhibitors in that it binds to CD4 receptors — the primary target of HIV infection. Since TNX-355 blocks HIV entry at a step prior to the co-receptor interaction, it is “co-receptor tropism independent,” with the ability to block both CCR5- and CXCR4-tropic viruses. The blockade presented by TNX-355 also does not depend on targeting a mutation-prone viral protein. TNX-355 has a Fast Track designation from FDA.
Trial briefs
AEterna Zentaris, Quebec City, Aug. 2 disclosed positive headline data from its Phase II trial with ozarelix (D-63153) for patients suffering from hormone-dependent inoperable prostate cancer. This open-label, randomized-controlled Phase II dose-finding trial originally designed for 48 patients was extended to 64 patients where four groups of 16 patients received different intramuscular [IM] dosage regimens of the luteinizing hormone releasing hormone (LHRH) antagonist, ozarelix, to assess its safety and efficacy. The study achieved its primary end-point of defining a tolerable dosage regimen of ozarelix that would ensure continuous suppression of testosterone at castration level (< 0.5 ng/ml) for a three-month test period. An important secondary efficacy end-point of the study aimed at assessing tumor response as determined by a 50% or greater reduction of serum PSA [prostate-specific antigen] levels, compared to baseline, was also achieved. Specifically, in this study, ozarelix IM 65 mg, 100 mg or 130 mg was administered according to different dosing schedules and repeated for three cycles of 28 days. The total dose by patient during the study ranged from 230 mg to 390 mg. The best results regarding the primary end-point of continuous suppression of testosterone were obtained at the upper limit of that range and especially with a dose of 130 mg per cycle where all patients remained suppressed to castration until at least day 85. Furthermore, in patients with continuous testosterone suppression below castration level, tumor response as measured by PSA levels was 97%. Ozarelix was well tolerated at all dosages. The detailed results from the study will be presented at the upcoming Societe internationale d’urologie meeting in Cape Town, South Africa, on Nov. 12, the company said. Ozarelix is a fourth-generation LHRH antagonist administered as a depot formulation for the treatment of hormone-dependent prostate cancer. The trial was conducted in Europe in collaboration with AEterna Zentaris’s partner Spectrum Pharmaceuticals, Irvine, CA. The company said it also has initiated, in collaboration with Spectrum Pharmaceuticals, an additional study that will enroll 32 patients at other European clinical sites to verify and optimize the findings derived from the cohort of patients having received 130 mg of ozarelix per cycle.
Celtic Pharmaceutical, Hamilton, Bermuda, Aug. 2, announced it has completed a further pivotal phase III trial of its lead compound, IDEA-033, in Europe, in which a total of 866 patients suffering with OA of the knee were entered into a placebo-controlled study lasting for three months with a further open-label extension phase also lasting three months. Three dose levels were used and the two higher doses (50 mg and 100 mg b.i.d. [twice daily, from Latin: bis in die]) were significantly superior to placebo in pain reduction (p<0.05 and p<0.01, respectively) at the end of the three-month trial period. Statistically significant treatment effects were observed after the first 24 hours of treatment. Of the 866 patients in the trial, 511 elected to enter the extension study, which will provide the firm with a significant data set covering the safety and efficacy of long-term use of IDEA-033. According to John Mayo, co-managing general partner of Celtic Pharma, these data results “constitute a major breakthrough in tackling the well-documented safety concerns associated with the chronic oral administration of NSAIDs (including COX-2 inhibitors) for pain relief.” In addition, Celtic announced that its investee company, IDEA AG, Munich, Germany, had acquired U.S. and Canadian rights from McNeill Consumer & Specialty Pharmaceuticals, a subsidiary of Johnson&Johnson, the terms of which were not disclosed. This provides IDEA with global control over the development and exploitation of the product. “Based on the positive Phase III clinical study results, we are extremely pleased to have now full control over IDEA-033. We have had a very good partnership with McNeil, but will now be able to promote the product development in USA and to benefit from the global market potential, which for our excellent product is demonstrably very large,” added IDEA AG CEO Gregor Cevc.
Cerexa, Alameda, CA, Aug. 2 announced positive top-line results for the Phase II clinical trial of Ceftaroline for the treatment of complicated skin and skin structure infections (cSSSI). This observer-blinded trial evaluated Ceftaroline versus standard therapy in 100 patients at 24 study sites worldwide. The clinical cure rate was 96.8% for subjects treated with Ceftaroline and 88.9% for those treated with standard therapy of vancomycin, with or without adjunctive aztreonam, in the clinically evaluable population. The microbiological response rate was 95.2% for the Ceftaroline group and 85.7% for the standard therapy group in the microbiologically evaluable population. Ceftaroline also demonstrated excellent activity against gram-positive and gram-negative organisms isolated from patients in the study, including 100% of MRSA [methicillin-resistant Staphylococcus aureus] isolates inhibited at 0.5 mg/L or less. Ceftaroline is a next-generation, broad-spectrum, injectable cephalosporin that combines the advantages of an enhanced gram-positive spectrum, including bactericidal anti-MRSA activity, with broad gram-negative activity. In March, FDA granted Ceftaroline Fast Track designation for the treatment of cSSSI caused by MRSA.
ChemGenix Pharmaceuticals, Grovedale, Victoria, Australia, Aug. 2 announced the recent publication of two clinical research papers that support the expansion of the clinical development of Ceflatonin (homoharringtonine or HHT) to include treatment of both newly diagnosed acute myeloid leukemia (AML) patients and those with advanced disease resistant to other therapies. Jean-Pierre Marie, M.D., of the Universite Pierre et Marie Curie in Paris published a study in the “British Journal of Cancer.” That Phase I study recruited 18 advanced-stage AML patients who had previously failed other AML treatments, and found that Ceflatonin had significant clinical benefits. Eleven of 12 patients with circulating leukemic cells showed significant improvement, two achieved complete remission and one chronic myelomonocytic leukemia patient in the latter stages of the disease (blast crisis) returned to chronic phase. Myelosuppression was the most common complication, occurring in all patients. In the second study, W-L Wu, M.D., Zhejiang University, China, published trial results in the journal “Leukemia.” The Phase II study of 48 patients concluded that Ceflatonin has potential as a first line therapy in combination with two other agents in young adult patients with AML. Ceflatonin in combination with cytarabine and aclarubicin resulted in complete remission in 83% of patients, with acceptable levels of toxicity.
Palatin Technologies, Cranbury, NJ, and King Pharmaceuticals, Bristol, TN, Aug. 3 announced results of Part 2 of a Phase IIa pilot study evaluating the effects of bremelanotide in post-menopausal women diagnosed with female sexual arousal disorder (FSAD). Results showed that on a 14-item questionnaire, 73% of the women reported an increased level of genital arousal while on bremelanotide compared with 23% of women on placebo. Also, 46% of women on bremelanotide reported an increased level of sexual desire while only 19% of women responded similarly after placebo treatment. Additionally, subjects receiving bremelanotide reported a higher incidence of engaging in sexual activity compared to placebo. Twenty-six women with a diagnosis of FSAD were enrolled at two investigational sites in this double-blind, randomized, placebo-controlled, single dose, crossover clinical study. All subjects enrolled in this clinical study were evaluated by an experienced clinical psychologist and were confirmed to have a diagnosis of FSAD. Subjects were administered a 20 mg dose (2 x 10 mg) of intranasal bremelanotide or placebo spray in a randomized manner and were monitored and evaluated for three hours post-dose before being discharged from the clinic. All subjects completed a Treatment Satisfaction Index questionnaire at 24-hours post-dose as a means of measuring their levels of sexual desire, genital arousal and, if applicable, satisfaction with sexual activity. AEs reported included nausea, headache and nasal congestion and were comparable to AEs reported for other clinical studies evaluating this dose. Bremelanotide is the first compound in a new drug class called melanocortin-receptor agonists under development to treat sexual dysfunction. This new chemical entity is being evaluated in Phase IIb clinical trials studying the efficacy and safety profile of varying doses of this novel compound in men experiencing erectile dysfunction (ED) and women experiencing female sexual dysfunction. The mechanism of action of bremelanotide may offer important benefits over currently available products for the treatment of ED because it acts on the pathway that controls sexual function without acting directly on the vascular system. The current study followed a similarly designed clinical study conducted with pre-menopausal patients with FSAD, the results of which were recently published in the July issue of the “Journal of Sexual Medicine.” Palatin and King said they plan to more fully present information regarding the results of this study at a future conference. The companies also said they are currently enrolling subjects in a 100-patient, Phase IIb at-home clinical trial in pre-menopausal FSAD patients at approximately 20 clinical sites throughout the U.S.
PDL BioPharma, Fremont, CA, Aug. 3 announced that a double-blind, placebo-controlled, Phase III clinical study of terlipressin, a vasoactive peptide, did not meet its primary endpoint in the treatment of type 1 hepatorenal syndrome (HRS), a life-threatening complication of advanced liver disease characterized by rapidly progressive kidney failure. In this study, the primary endpoint was treatment success, defined as the percentage of patients alive at Day 14 who demonstrated reversal of type 1 HRS, based upon two measurements of serum creatinine levels less than or equal to 1.5 mg/dL without dialysis or recurrence of disease. The data [not provided in the press statement] showed a positive trend toward treatment success, but did not reach statistical significance. “We are disappointed that the trial of terlipressin did not meet its primary endpoint, as there is a substantial unmet need in HRS,” said Steven Benner, M.D., chief medical officer, PDL. “We will work with Orphan Therapeutics to further analyze the study results.” PDL obtained U.S. commercial rights to terlipressin following its acquisition of ESP Pharma in March 2005. The original agreement between ESP Pharma and Orphan Therapeutics was established in June 2004. This Phase III study, conducted by Orphan Therapeutics, was the first randomized, double-blind, placebo-controlled clinical trial of terlipressin in type-1 HRS in the U.S. The study, which evaluated the safety and the potential effect of terlipressin on kidney function and survival in patients with type 1 HRS, enrolled 112 patients at 30 liver disease centers in the U.S. and five centers outside the U.S.. Patients were randomized to receive terlipressin or placebo every six hours until a reversal of HRS was seen or for up to 14 days.
Pfizer’s Sudafed PE is ineffective, according to researchers at the University of Florida. According to the researchers, the new OTC nasal decongestant contains the compound phenylephrine, which is not sufficiently absorbed into the bloodstream to make it an effective oral medication. Pfizer changed its active pharmaceutical ingredient in the product last year, after FDA acted on complaints that criminals were buying up bulk quantities of Sudafed tablets and generic look-alikes for their initial key ingredient, a compound known as pseudoephedrine. Police say pseudoephedrine is being used in clandestine labs, where it is turned into a highly potent, illegal methamphetamine. Although pseudoephedrine — a long-used, effective decongestant — is still available without prescription, FDA has ordered pharmacies to pull Sudafed and similar tablets from open shelves by Sept. 30 and keep them behind the counter. The government also wants pharmacies to ask for identification from customers buying Sudafed, maintain a log of buyers and limit daily purchases. A Pfizer spokesperson appeared unconcerned by the move. He insisted the new Sudafed PE with phenylephrine is effective and added that consumers can still ask for the original Sudafed [which will be kept behind the counter] if they want it.
Tufts-New England Medical Center-researchers, in a comprehensive review of published clinical studies, announced Aug. 3 they have found that increased consumption of DHA [docosahexaenoic acid] and EPA [eicosapentaenoic acid] (omega-3’s), “reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke.” In the review, which was published in the “American Journal of Clinical Nutrition,” the researchers identified 46 unique eligible studies on dietary omega-3 and cardiovascular disease. These included outcomes that lasted more than one year, including 14 randomized clinical trials, 25 prospective cohort studies and seven case-control studies. The researchers noted that studies published in peer-reviewed journals indicated that patients with cardiovascular disease, diabetes, rheumatoid arthritis and depression may be deficient in vital nutrients, including omega-3, folic acid, and vitamins B6 and B12. According to Barbara Levine, M.D., Weill Cornell Medical College, “Increasing the intake of omega-3 fatty acids, including DHA and EPA, has been clinically shown to reduce severity of these diseases, so that patients are often able to reduce or eliminate medications that have serious AEs.”
Conferences
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