Drug Trials In SA Seeing Promising ResultsShare This Page
Drug Trials In SA Seeing Promising ResultsShare This Page
Phase 2 clinical trial begins for a novel monoclonal antibody
Boston, Mass. — Following a successful Phase 1 study for safety, researchers at MassBiologics of the University of Massachusetts Medical School (UMMS) today announced the beginning of a Phase 2 clinical trial testing the ability of a human monoclonal antibody they developed to prevent hepatitis C virus (HCV) infection of a donor liver in transplant patients.
The first patients were enrolled in the study in December. The primary goal of this randomized, double-blind, placebo-controlled study is to test if the monoclonal antibody, designated MBL-HCV1, prevents re-infection of patients chronically infected with HCV who are undergoing liver transplantation.
MassBiologics plans to enroll 16 patients in the first part of the study. “We are hopeful that positive results from this study will meet an important public health need, and we could not take this important step without the willing and thoughtful participation of these volunteers,” said Donna Ambrosino, MD, executive director of MassBiologics and a professor of pediatrics at the Medical School.
There are currently five hospitals participating in the trial—Massachusetts General Hospital, Beth Israel Deaconess Medical Center, both in Boston, Lahey Clinic in Burlington, Massachusetts, Yale-New Haven Hospital in Connecticut and Mount Sinai Hospital in New York City—and others may join in the coming months. The first six patients enrolled have come from three of these sites.
HCV damages the liver and is the leading indication for liver transplantation, diagnosed in about half of the 6,000 patients who receive liver transplants each year in the United States. According to the US Centers for Disease Control and Prevention, 3.2 million Americans are chronically infected with HCV and approximately 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection.
For patients with end-stage liver disease from HCV infection, liver transplantation is the only option. While it can be a life-saving treatment, transplantation does not cure the disease. In nearly all cases, the patient’s new liver is eventually infected by HCV because the virus remains in the patient’s bloodstream during surgery. The course of recurrent HCV disease is accelerated after transplantation and up to 20 percent of transplant patients develop cirrhosis within five years. Unfortunately, the standard antiviral drugs currently used to treat HCV prior to the onset of end-stage liver disease are poorly tolerated after liver transplantation, leaving these patients with few options.
To address this unmet medical need, the team at MassBiologics, working in collaboration with investigators Gyongyi Szabo, MD, PhD, professor of medicine, and Robert Finberg, MD, professor and chair of the Department of Medicine at UMMS, set out to develop a human monoclonal antibody that could clear HCV from a patient’s bloodstream and protect the donated liver from infection. In pre-clinical studies, MBL-HCV1 successfully neutralized the virus in cell culture and animal models of infection. A Phase 1 study in 31 healthy volunteers completed in 2009 showed the antibody was well tolerated, with no serious side effects. The Phase 1 study also measured the levels of the antibody in the bloodstream and its ability to bind and inactivate the virus, thereby helping to establish the dosage and protocol for the Phase 2 study now under way.
In the current study, patients will be randomized to receive an infusion of either the antibody or placebo between one and four hours prior to surgery. Then, during the phase of surgery when the diseased liver is removed, but before the donor liver is implanted, patients will receive a second infusion of either the antibody or placebo. After the surgery is completed, the patients will receive a third infusion, and then daily infusions during the first week of recovery. A final infusion is administered on the 14th day after liver transplantation.
“The liver is the main reservoir for the hepatitis C virus,” said Brett Leav, MD, senior director of clinical affairs at MassBiologics. “The virus circulates in the blood, but only resides and replicates in the liver. So the idea here is to clear the virus from the bloodstream before it has an opportunity to re-infect the new liver.”
After transplantation, patients’ blood will be tested on a regular basis to screen for reemergence of HCV, which is usually detected within the first week after transplantation. The primary goal of the Phase 2 trial is to see if the patients who received the antibody are free of HCV at 42 days after transplantation. An interim analysis is planned after the first 16 patients have been enrolled in the trial, and a Data Safety and Monitoring Board overseeing the study will assess the effectiveness and safety of MBL-HCV1.
By LAURAN NEERGAARD
AP Medical Writer
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.
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.
Hepatocellular carcinoma (HCC) is the fifth most common neoplasia, In former times, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently , in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. .
Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC.Case presentationAn 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department.
Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started.
Right from one month after the treatment start, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk.
At the sixth month the normalization of alpha-fetoprotein level at the lower limit of normality was confirmed and MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was obserdved.
At present the patient is in a follow-up programme to evaluate the duration of the complete response.
Conclusions: This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.
Author: Rodolfo SaccoIrene BargelliniGianluigi GiannelliMarco BertiniElena BozziEmanuele AltomareValentina BattagliaAntonio RomanoMichele BertoniAlfonso CapriaGiampaolo BresciCarlo Bartolozzi
Credits/Source: BMC Gastroenterology 2011, 11:4
Copyright by the authors listed above – made available via BioMedCentral (Open Access).
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Dale Shaylor journeyed to Florida in search of a life-saving liver transplant — only to find the surgery has a price tag far out of the missionary pilot’s reach.
Shaylor, a Deltona father of three who has Hepatitis B, said he was told that to get on a list to receive a new liver from a cadaver, he would have to make a deposit of nearly half a million dollars — $425,000 to be exact.
“A transplant is not something that’s covered as an emergency — it’s more of a luxury item,” said Shaylor, 40, referring to what he’s learned in the last month about his options.
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Tampa, Fla. (Jan. 10, 2011) – Transplanting their own (autologous) bone marrow-derived stem cells into 48 patients with end-stage liver disease resulted in therapeutic benefit to a high number of the patients, report researchers publishing in the current issue of Cell Transplantation (19:11). Yet, the mechanism by which the infusion of CD34+ stem cells improves liver function remains elusive, they say.
The study, carried out by a team of researchers in California and in Egypt, is now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/.
According to the study’s corresponding author, Dr. Mark A. Zern of the University of California Davis Medical Center, Sacramento, CA, patients with end-stage liver failure in Egypt have few treatment options but for transplantation. A shortage of donors and cost factors make that strategy unrealistic. Accordingly, this study sought to evaluate the safety and efficacy of transplanting autologous bone marrow-derived CD34+ stem cells in 48 patients, 36 of whom had chronic, end-stage hepatitis C-induced liver disease, and 12 with end-stage autoimmune liver disease.
“For all patients there was a statistically significant decrease in peritoneal cavity fluid, or ‘ascites,'” said Dr. Zern. “There was also clinical and biochemical improvement in a large percentage of patients who received the transplantation.”
The researchers reported that they obtained “reasonable numbers of CD34+ cells” that were then “amplified and partially differentiated into hepatocyte precursor cells.”
“This enabled us to transplant as many as one billion of these cells per patient,” explained Dr. Zern. “The finding of improvement in ascites in a significant number of patients is impressive and somewhat surprising, suggesting that cell transplantation might be clinically significant beyond the improvement in laboratory parameters.”
They also report using granulocyte-colony stimulating factor (G-CSF) to “mobilize…CD34+ stem cells into peripheral circulation.” The researchers anticipated that G-CSF would likely enhance a variety of circulating bone marrow-derived cells, producing growth factors which could “positively affect liver regeneration and perhaps have a positive effect on portal hypertension.”
The team also reported that prior to transplantation, the cells were already beginning to develop a hepatocyte phenotype while in culture, suggesting that the cells may have acted as hepatocyte-like cells following engraftment. The researchers plan to compare routes of infusion to determine if peripheral infusion of transplanted cells will be adequate.
“The use of peripheral infusion would dramatically reduce both costs and risks for this cell transplantation, thus making the treatment an even more viable option in Egypt and throughout the world,” concluded Dr. Zern.
“It would be very interesting to determine if the differentiation to hepatic precursors was a necessary step for this treatment,” said Dr. Stephen Strom, a professor of pathology in the Department of Pathology at the University of Pittsburgh and section editor for Cell Transplantation. “Other research groups are now showing similar results with cells without any hepatic characteristics, including fractionated and unfractionated bone marrow and mesenchymal stem cells. Taken together, these data suggest that the positive effects these researchers find may be the result of paracrine effects from factors secreted by the donor cells. I look forward to reading about the outcome of future studies to determine the optimal route of administration and dose of these cells, as well as more long term follow up.”
TUSTIN, CA — (MARKET WIRE) — 01/10/11 — Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced that it has initiated a randomized Phase II clinical trial in patients with previously untreated genotype-1 hepatitis C virus (HCV) infection. This open-label trial will determine the early virologic response (EVR) rate of patients after 12 weeks of therapy with Peregrine’s bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating potential, in combination with the antiviral drug ribavirin versus standard of care, pegylated interferon alpha 2a and ribavirin. Peregrine expects to complete enrollment shortly in an ongoing Phase Ib HCV trial and report data by mid-year.
“Our fourth randomized Phase II trial evaluating bavituximab for oncology and viral infections is designed to build on our three prior Phase I HCV trials, which have demonstrated our antibody’s acceptable safety and promising signs of antiviral activity,” said Steven W. King, president and chief executive officer of Peregrine. “Although there are several targeted antiviral drug candidates in development against HCV, immune stimulation with interferon remains a cornerstone of the standard HCV regimen, but unfortunately causes serious side effects and unacceptable toxicity for many patients. With bavituximab’s immune reactivation mechanisms and safety profile to date, we are eager to assess this new combination as a potential alternative to interferon-based regimens for patients infected with HCV.”
Bavituximab may address a fundamental “immune evasion” mechanism exploited by many infectious pathogens. A growing body of published data from researchers worldwide shows that bavituximab’s PS target, exposed on the surface of cells infected by viruses and protozoan parasites, suppresses the immune system’s ability to fight disease. PS-targeting antibodies such as bavituximab bind to PS and block the immunosuppressive signals created by the target, thereby allowing the immune system to mount a robust immune response against the pathogen. In prior HCV clinical trials, bavituximab administered as monotherapy in single and multiple doses demonstrated a positive safety profile with no dose-limiting toxicities or serious adverse events. Bavituximab as a monotherapy also showed promising on therapy antiviral activity of up to 1.5 log viral load reduction.
About the Phase II HCV Trial
In this multicenter Phase II randomized, open-label trial, up to 66 patients with previously untreated genotype-1 chronic HCV infection will be randomly assigned to one of three treatment arms. Patients will receive daily oral ribavirin (1000 mg) with either weekly bavituximab (0.3 mg/kg or 3 mg/kg) or PEG-IFN alpha-2a (180 µg) for up to 12 weeks and will be tested for safety parameters and antiviral activity.
The primary endpoint of the study is the proportion of patients achieving early virologic response (EVR), an early predictor of which patients are likely to clear virus with continued treatment. EVR is defined as a greater than or equal to 2 log reduction in HCV RNA after 12 weeks of treatment. Secondary endpoints include safety, tolerability and HCV viral kinetics. For further information about this trial, please visit www.peregrinetrials.com or http://www.clinicaltrials.gov/ct2/results?term=bavituximab.
About Bavituximab’s Antiviral Approach
Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body’s immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.
Researchers have found that PS is exposed on the outer membrane of cells infected with HCV, HIV, influenza, herpes viruses, hemorrhagic fever viruses, respiratory syncytial virus, measles as well as other viruses. A growing body of scientific publications, including Nature Medicine and The Journal of Experimental Medicine, has highlighted data on the role of PS and Peregrine’s PS-targeting therapies in infectious diseases.
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at www.peregrineinc.com.
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SAN FRANCISCO–(BUSINESS WIRE)–Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) today announced its 2011 business objectives in conjunction with the 29th Annual J.P. Morgan Healthcare Conference in San Francisco. Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex, will discuss these objectives as part of a live webcast presentation, which will be available on Vertex’s website, www.vrtx.com, on Monday, January 10 at 9:30 a.m. PT (12:30 p.m. ET).
“2011 will be a landmark year for Vertex as we prepare for the expected launch of telaprevir in hepatitis C and advance other new therapies in development,” said Mr. Emmens.
“Our commercial team is in place and prepared for the planned launch of telaprevir this year. We believe that telaprevir will dramatically change the treatment of hepatitis C and establish Vertex as a company capable of discovering, developing and launching transformative medicines to treat serious diseases.
“We are in a unique position, as just behind telaprevir is VX-770, a medicine in development that aims to treat the underlying cause of cystic fibrosis. We will soon obtain data from the Phase 3 registration program of VX-770 that may support the planned submission of a New Drug Application to the FDA in the second half of this year.
“We also expect to receive important data from multiple ongoing Phase 2 trials this year, including those evaluating new combination regimens for hepatitis C and cystic fibrosis, which may provide further development opportunities,” Mr. Emmens concluded.
Hepatitis C: Preparing for Launch of Telaprevir
Submission of New Drug Application Completed in November 2010 with Request for Priority Review
Phase 3b Study of Twice-daily Dosing of Telaprevir to Support Supplemental NDA by end of 2012
Opportunities to Further Advance Future Treatment of Hepatitis C
Interim Data from Phase 2 Study of Telaprevir and VX-222 Expected in First Quarter of 2011
Additional Trials of Telaprevir to Advance Leadership Position in Hepatitis C