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Protalix Shows Positive Results in Phase 3 – Plant Cells to the Rescue
This week, Protalix Ltd. announced positive top-line results of their Phase III study of prGCD in treatment-naive patients with Gaucher disease.
The prGCD drug development program has been a prime example of a true Sponsor/CRO partnership. Beginning in 2004, Target Health Inc., based in NYC was the full-service CRO for Protalix Ltd., based in Israel. Together, we took prGCD, for the treatment of Gaucher Disease, from pre-IND to toxicology to completion of the Phase III clinical program in 5 years. Fulfillment of these aggressive timelines would have been impossible without the complete respect and cooperation between the 2 companies, and the eClinical trial software suite of Target e*CRF® for EDC, Target Document® for the paperless TMF and Target Encoder® for AE and medication coding.
prGCD met all of the key clinical endpoints. Importantly, the rates of hypersensitivity reactions and antibody formation suggested prGCD is as safe as Cerezyme (Genzyme), and should remove any remaining concerns about immunogenicity potential of a plant-produced protein. At both 60U/kg and 30U/kg doses, prGCD improved mean reduction in spleen volume vs. baseline (p<0.0001) at 9 months as well as statistically significant improvements in liver size and hemoglobin levels. Protalix makes prGCD using plant cells grown in vitro and has a fantastic platform for drug development.
For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com
A Personalized Antibody Library…and more
Theraclone Sciences, based in Seattle, has a proprietary technology that can create an entire immune history from a person’s 1) ___ sample. The end result is a personalized antibody library covering every disease that an individual has successfully fought off. The company has previously used this technology to identify 2) ___ against HIV and is now turning to influenza by examining blood from patients who successfully fought off some of the most lethal flu viruses. By studying how the patients’ antibodies react to H5N1 influenza, it was found that the most effective antibodies bound to a spot that appears conserved among all 3) ___ strains, a specific location on a known surface protein called M2. Scientists will look at the crystal structures of these antibodies and then use them as templates to reverse-engineer a vaccine that would prompt the human 4) ___ system to produce them. Theraclone feels that it may be able to come up with immunogens that bind to the broadly neutralizing antibodies. But whether they’re capable of eliciting the same or similar antibodies on 5) ___ is really the big unknown right now.” Theraclone is beginning an $18 million collaboration with Tokyo-based Zenyaku Kogyo pharmaceutical company to look for conserved flu antibodies and develop subsequent vaccine candidates. Perhaps the most exciting but challenging prospect for a universal vaccine lies in DNA-based vaccines, sequences of DNA that, when taken up by cells and expressed as 6) ___, prompt an immune response. DNA vaccines can be made and modified quickly, are cheap to produce, and have a long 7) ___ life. The major hurdle in developing these vaccines is getting the right cells to take up enough DNA to elicit immunity. Inovio, a company based in Blue Bell, PA, is working to solve this problem through a process called electroporation, in which a small electric shock disrupts a cell membrane long enough for designer DNA fragments to slip through. Recent studies by the company have shown that consensus genes, synthetic sequences that look similar enough to certain components in a variety of viruses, can prompt a broad immune response against multiple strains of flu. Despite the promise, vaccine researchers still have a long road to travel. There’s lots of exciting vaccines out there, but the first thing with vaccines is their 8) ___.
ANSWERS: 1) blood; 2) antibodies; 3) viral; 4) immune; 5) vaccination; 6) proteins; 7) shelf; 8) safety
Aspirin Misuse May Have Made 1918 Flu Pandemic Worse
The devastation of the 1918-1919 influenza pandemic is well known, but a new article, published in Clinical Infectious Diseases (1 November 2009) suggests that the misuse of aspirin was a surprising factor in the high death toll. High aspirin dosing levels used to treat patients during the 1918-1919 pandemic are now known to cause, in some cases, toxicity and a dangerous build up of fluid in the lungs. These responses to aspirin may have contributed to the incidence and severity of symptoms, bacterial infections, and mortality. Autopsy reports from 1918 are consistent with what we know today about the dangers of aspirin toxicity, as well as the expected viral causes of death. The motivation behind the improper use of aspirin is a cautionary tale as physicians did not fully understand either the dosing or pharmacology of aspirin, yet they were willing to recommend it. Its use was endorsed by doctors wanting to “do something,” and accepted by families and institutions desperate for hope. Adapted from materials provided by Infectious Diseases Society of America.
Investment in Parkinson’s Disease Data Bank Yields Potential Therapy
Parkinson’s disease attacks cells in the brain that regulate movement by releasing a chemical called dopamine. The loss of those cells leads to progressively disabling symptoms, including involuntary shaking, slow movement, stiffened muscle tone, and impaired balance. Levodopa, a precursor of dopamine, provides some relief from those symptoms but does not alter the disease course. Urate (or uric acid) is a product of the body’s metabolism. Diets high in liver, seafood, and dried beans and peas tend to cause higher levels of urate in the blood, and are also associated with gout – a painful buildup of urate crystals in the joints. Urate is a natural antioxidant, and many studies have found that antioxidants slow the course of Parkinson’s disease in animal models. Also, prior research has shown that people who have gout or who consume foods associated with high urate have a lower incidence of Parkinson’s disease.
According to an article published online in Archives of Neurology (12 October 2009), individuals with Parkinson’s disease who have higher levels of a metabolite called urate in their blood and in cerebrospinal fluid (CSF) have a slower rate of disease progression. A clinical trial is now under way to examine the safety and potential benefits of supplemental urate elevation for recently diagnosed Parkinson’s patients who have low urate levels. Investigators demonstrated the link with urate by mining a repository of clinical data and tissue samples collected from Parkinson’s patients more than 20 years ago as part of a pioneering study called DATATOP, funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). The study illustrates the value of saving data and biospecimens from large clinical studies, and making them available for future research. It was emphasized that while the data are quite intriguing, there is no proof that elevating urate levels will help against Parkinson’s disease. Thus, urate supplementation should not be attempted outside of a clinical trial, where physicians can closely monitor possible benefits and risks, such as gout and heart disease.
The Parkinson Study Group was the first to examine whether urate levels are related to the course of Parkinson’s disease. Last year, after mining data from another large clinical trial, they reported that high levels of urate in blood were associated with a slower disease course. The current observation is an expansion of that work and the first time that investigators have looked for a connection between the course of Parkinson’s and levels of urate in CSF, the fluid that fills spaces in the brain and spinal cord.
The DATATOP trial began in the late 1980s, and was designed to test whether vitamin E, the drug deprenyl (selegiline), or a combination of both could slow the course of early-stage Parkinson’s disease. The trial enrolled 800 patients and followed them for two years. Deprenyl, which inhibits the breakdown of dopamine, was found to provide short-term relief from symptoms. Vitamin E showed no significant benefit. As part of the DATATOP trial, samples of blood and CSF were acquired from more than 90% of the participants at enrollment. In the new study, the researchers analyzed whether blood and CSF urate levels were related to the course of Parkinson’s by relying on blood measurements done at the time of the DATATOP trial and by taking new measurements from the 20-year-old, frozen samples of CSF. Looking across all of the treatment groups in the study, it was found that patients with the highest urate levels in their blood and CSF had a slower functional decline as measured by their need for levodopa treatment. The results suggest that urate elevation might slow the course of Parkinson’s in patients with early-stage disease and low urate levels. The Safety of URate Elevation in Parkinson Disease (SURE-PD) study, led by Dr. Schwarzschild, is a placebo-controlled trial designed to test that hypothesis. Patients in the treatment arm of the trial will take daily, oral doses of a urate precursor called inosine for up to two years. The trial is funded by the Michael J. Fox Foundation, and is recruiting recently diagnosed patients who do not yet require Parkinson’s medication at 11 sites across the United States. For more information, visit <www.clinicaltrials.gov> and search by the identifier NCT00833690.
Gene Mutation Linked to Type of Childhood Cancer
Rhabdomyosarcoma (RMS) is the most common type of sarcoma found in children. This aggressive cancer can occur in many places in the body, but it usually begins in cells that form muscle tissue. Although progress has been made in increasing the overall survival of patients treated for RMS, less than 30% of children whose cancer has spread, or metastasized, survive more than five years. According to an article published online in the Journal of Clinical Investigation (5 October 2009), a gene has been identified that may play a role in the growth and spread of RMS, as well as reveal a potential new target for treatment. The newly implicated gene produces a substance called fibroblast growth factor receptor 4, also referred to as FGFR4 protein. This protein belongs to a family known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival, as well as the formation of new blood vessels. Mutations in receptor tyrosine kinase genes have been found previously in some other human cancers. Some of these mutations cause the tyrosine kinase to be active in the absence of an external signal that is normally required for activation. This inappropriate activation may promote the development of cancer. Earlier research by this team and others had shown that the FGFR4 gene is highly expressed in RMS tumors. The gene is also expressed during muscle development but not in mature muscle cells. Although this finding suggested a role for FGFR4 protein in RMS, the way in which it might contribute to the disease was not known. In the new study, the team first examined FGFR4 gene expression in RMS tumors from patients for whom clinical follow-up data were available. The researchers found that high levels of FGFR4 gene expression were associated with advanced disease, including metastasis, as well as poor patient outcome. They next used genetic manipulation techniques to block the expression of the FGFR4 gene in human RMS cells. Suppression of FGFR4 gene expression slowed the growth of the cells in laboratory experiments. In addition, when these cells were transplanted into mice, they grew more slowly and were less likely to spread to the lungs than cells with unsuppressed FGFR4 genes. The team next looked for mutations in the FGFR4 gene in 94 human RMS tumors obtained from the NCI-funded Cooperative Human Tissue Network and Children’s Hospital. They found that more than 7% of the tumors had mutations causing alterations in the tyrosine kinase portion of the FGFR4 protein. Four different mutations, two in each of two locations in the FGFR4 gene, were predicted to change the function of the FGFR4 protein. In laboratory studies, it was found that two of the mutations produced proteins that were able to promote their own activation, a hallmark of tyrosine kinase mutations that are associated with cancer. The mutations also appear to be involved in activation and suppression of cell signaling pathway components which have been associated with cell growth and survival in RMS and other cancers and with metastasis. Additionally, the researchers found that, when RMS cells had the mutations, they were more sensitive to treatment with drugs that inhibit FGFR4 activity. Thus, a mutated FGFR4 gene may represent an Achille’s heel in RMS. According to the authors, the findings represent the first known mutations in a receptor tyrosine kinase in RMS, and that when FGFR4 is overactive, either due to increased expression or mutations, it plays a key role in the growth and spread of RMS. The authors added that high-risk or metastatic cancers may harbor other critical, as yet undiscovered, mutations. The search through the genome for every mutation that may contribute to pediatric and other cancers, increases the likelihood for personalized or individualized treatment.
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Fast Track Designation
Section 506(a)(1) of the Food Drug and Cosmetic Act states that a drug designated as a fast track product is intended for the treatment of a serious or life-threatening condition and demonstrates the potential to address unmet medical needs for the condition. The fast track classification thus does not apply to a product alone, but applies to a combination of the product and specific indication for which it is being studied. The indication includes both the condition for which the drug is intended (e.g., heart failure) and the anticipated or established benefits of use (e.g., improved exercise tolerance, decreased hospitalization, increased survival). It is, therefore, the development program for a specific drug for a specific indication that will receive fast track designation.
For a condition to be serious, the condition should be associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient but the morbidity need not be irreversible, providing it is persistent or recurrent. All conditions meeting the definition of life-threatening as set forth at 21 CFR 312.81(a) would also be serious conditions. Determination of the seriousness of a condition is a matter of judgment, but generally is based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. Thus, acquired immunodeficiency syndrome (AIDS), all other stages of human immunodeficiency virus (HIV) infection, Alzheimer’s dementia, angina pectoris, heart failure, cancer, and many other diseases are clearly serious in their full manifestations. Further, many chronic illnesses that are generally well-managed by available therapy can have serious outcomes such as inflammatory bowel disease, asthma, rheumatoid arthritis, diabetes mellitus, systemic lupus erythematosus, depression, psychoses, and many other diseases.
In making a fast track determination, FDA will assess whether the development program is designed to demonstrate an effect on a serious aspect of the condition. The following examples illustrate FDA’s approach:
- A therapeutic directed at some aspect of a serious condition for effects on a serious manifestation(s) or serious symptom(s) of the condition.
- A diagnostic to improve diagnosis or detection of the condition and scientific data provided a strong basis for a presumption that the improvements in diagnosis or detection of the condition would lead to improved outcome.
- A preventive product for a serious manifestation(s) of the condition.
- A product intended to ameliorate or prevent a side effect of therapy if the side effect were serious
An unmet medical need is a medical need that is not addressed adequately by an existing therapy where there is no available therapy for the condition. An unmet medical need also occurs when a product has the ability to provide benefit(s):
- a. in patients who are unable to tolerate or are unresponsive to alternative agents (e.g., an antipsychotic agent that is effective in people failing standard therapy), or an ability to be used effectively in combination with other critical agents that cannot be combined with available therapy.
similar to those of alternatives while avoiding serious toxicity that is present in existing therapies, or avoiding less serious toxicity that is common and causes discontinuation of treatment of a serious disease.
Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.