UPMC was placed on probation today for up to a year by a national agency that regulates organ transplant surgeries after a kidney transplant surgery this year in which a male patient accidentally contracted Hepatitis C from his female companion donor.
"They have been quite satisfied with the plan of correction," Dr. Abhi Humar, UPMC chief of transplantation, told the Tribune-Review. "They're not going to take a one-time snapshot. This allows them to have that degree of oversight."
The designation by the United Network for Organ Sharing means that UPMC has agreed to take steps to correct the problem, the agency said in a statement after board members voted this morning.
"This finding is the result of a series of detailed medical peer reviews," Dr. John Lake, UNOS president, said in a statement.
UPMC "has identified a need for process improvement in communicating key clinical information among transplant staff members," he stated. "While the center has acted quickly and responsibly to identify and implement a corrective action plan, we believe probation is warranted."
UPMC suspended a nurse and demoted a surgeon in connection with the case.
The probationary period could last up to a year from October when UPMC started taking steps to add more oversight, Humar said. Where UPMC had two steps before to prevent an organ transplant recipient from contracting disease from a donor, it now has seven, he said.
"We didn't have enough redundancies built into the system," Humar said.
During the probationary period, UNOS officials will monitor UPMC's program to make sure that it continues with the new steps it has put into place. That oversight, however, will not delay or change patients' access to transplant surgeries or services, Humar said.
Christina Mecannic of Morgan in Greene County underwent surgery on April 6 at UPMC Montefiore to give one of her kidneys to Michael Yocabet, the father of their 18-year-old son. The couple found out a month later that Mecannic is infected with the hepatitis C virus and had unknowingly passed it to Yocabet during the transplant.
Mecannic and Yocabet filed separate lawsuits in Allegheny Common Pleas court. They name as defendants Drs. Henkie Tan, Mark Sturdevant, Jennifer L. Steel and Nirav Shah, Nurse Mimi Funovits, and others in the UPMC transplant program.
UPMC reopened its live-donor liver and kidney transplant programs in July, two months after voluntarily suspending them without explanation. The Trib first reported the programs' suspension and later that it was the result of a heptatitis C-infected liver donor whom officials had missed.
The live-donor kidney transplant program at Children's Hospital also was temporarily shuttered by the suspension of the UPMC programs because it relies mostly on adult donors.
Several patients had surgeries that were delayed because of the shutdown, but all of them elected to wait and receive the transplant at UPMC after the programs restarted, he said.
Optimizing cost-effectiveness in perioperative care for liver transplantation
The latest issue of Liver Transplantation reports on a model for low- to medium-income countries for perioperative care for liver transplantation.
Although liver transplantation is a highly effective treatment, it has been considered too costly for publicly funded health systems in many countries with low to medium average incomes.
However, with economic growth and improving results, some governments are reconsidering this position.
Cost-effectiveness data for liver transplantation are limited, especially in perioperative care, and the techniques and costs vary widely between centers without overt differences in outcomes.
Anesthesiologists working in new programs find it difficult to determine which modalities are essential, which are needed only in exceptional circumstances, and which may be omitted without effects on outcomes.
Dr John Klinck and colleagues from California, USA investigated key elements of preoperative evaluations, intraoperative management, and early postoperative care that might significantly affect costs in order to develop a best-value approach for new programs in resource-limited health systems.
The research team identified all modalities of care commonly used in anesthesia and perioperative care for adult liver transplantation along with their costs.
Recommended modalities included preoperative echocardiography
Liver Transplantation
Those considered to be universally accepted as minimum requirements for safe care were excluded from the analysis, and so were those considered to be safe and low-cost, even when evidence of efficacy was lacking.
The researchers found that remaining items were, therefore, those with uncertain or context-restricted value and significant costs.
A systematic review of the published evidence, practice surveys, and institutional guidelines was performed, and the evidence was graded and summarized.
With respect to costs and benefits, each modality was then cited as strongly recommended, recommended or optional, or no recommendation was made because of insufficient evidence.
The team identified 16 modalities, which included preoperative cardiovascular imaging, venovenous bypass, pulmonary artery catheterization, high-flow fluid warming devices, drug therapies for hemostasis, albumin, cell salvage, anesthetic drugs, personnel requirements, and early extubation, were assessed.
Only high-flow fluid warming was strongly recommended.
The team reported that recommended modalities included preoperative echocardiography, cell salvage, tranexamic acid and early extubation.
The research team noted that 6 others were rated optional, and there was insufficient evidence for 5 modalities.
Dr Klinck's team comments, "We conclude that some costly techniques and treatments can be omitted without adverse effects on outcomes."
Liver Transplantation 2011: 17(11): 1247–1278
15 November 2011
Association for the Study of Liver Diseases San Francisco 2011 Nov 6-9
AASLD: Virus Shuts Down Liver Cancer in Early Trials
By Charles Bankhead, Staff Writer, MedPage Today
Published: November 14, 2011
Reviewed by Dori F. Zaleznik, MD;
Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- Patients with advanced hepatocellular carcinoma (HCC) appeared to gain a survival benefit when treated with the higher of two doses of an investigational oncolytic virus, results of a small, phase II trial showed.
Treatment with the higher dose of JX-594 was associated with a median overall survival of 13.8 months as compared with 6.7 months in patients who received a lower dose.
Subgroup analysis showed a consistent survival benefit in patients who had prior exposure to chemotherapy for HCC and in patients who had multiple tumors.
The findings have provided impetus for larger phase IIb and phase III randomized clinical trials, as reported here at the American Association for the Study of Liver Diseases.
"This is the first demonstration of a benefit in survival with gene or virotherapy in cancer," said Tony Reid, MD, PhD, of the University of California San Diego.
"The safety of JX-594 has been documented in studies of intravenous and intratumoral administration involving more than 120 patients," he added.
JX-594 is the first member of a new class of targeted oncolytic poxvirus. The agent causes tumor necrosis via selective oncolysis and induction of granulocyte macrophage-colony stimulating factor, resulting in "vascular shutdown" and tumoral anti-immunity, said Reid.
Preliminary clinical studies of the poxvirus demonstrated replication, transgene expression, and evidence of response in patients with advanced liver cancer treated with intravenous or intratumoral administration (Lancet Oncol 2008; 9: 533-542, Nature 2011; 477: 99-102).
Reid presented findings from a randomized trial involving 30 patients with heavily pretreated advanced HCC. The patients were randomized to one of two doses of JX-594: 1 x 109 plaque forming units (pfu) or 1 x 108 pfu. The poxvirus was administered via three intratumoral injections separated by two-week intervals.
Patients randomized to the higher dose had received an average of 4.7 prior therapeutic interventions, and patients in the low-dose arm had received an average of 2.2 prior interventions. Prior treatment included systemic therapy in 38% of the high-dose group and 7% of the low-dose group.
A majority of patients in both groups had virus-related liver cancer. About half of the patients had four or more visible tumors.
Overall, 54% of patients had evidence of a necrotic response by modified Choi criteria at eight weeks, and the proportion of responding patients did not differ significantly between the high- and low-dose groups. Reid said that 52% of the patients had stable disease at eight weeks.
The twofold increase in overall survival in the high-dose arm reached statistical significance (P=0.029). Patients with a history of prior systemic therapy had a median overall survival of 13.8 months in the high-dose arm versus an expected three months from historical data, said Reid. Patients with multiple tumors had a median overall survival of 13.5 months with the higher dose of JX-594 versus 4.3 months with the lower dose (P=0.019).
Adverse events that occurred in at least 30% of patients consisted of fever, chills, injection-site pain, vomiting, nausea, abdominal pain, headache, anorexia, and fatigue. Few events reached grade 3 severity, and no grade 4-5 adverse events occurred.
The phase IIb trial of JX-594 has already begun. Reid said the phase IIb trial has an accrual target of 120 patients with advanced HCC that is refractory to sorafenib (Nexavar). The patients will be randomized 2:1 to JX-594 plus best supportive care (BSC) or to BSC alone.
The phase III trial will evaluate JX-594 as first-line therapy for patients with advanced HCC, comparing the oncolytic virus to standard of care.
Both studies have a primary endpoint of overall survival.
Slides/Data From NATAP
Enoxaparin Ups Survival in Cirrhotic Portal Vein Thrombosis
November 15, 2011 (San Francisco, California) — A new treatment regimen with the low-molecular-weight heparin enoxaparin reduced the incidence of portal vein thrombosis (PVT), leading to fewer events of clinical decompensation and enhanced survival in patients with advanced cirrhosis, according to data presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
"PVT occurs in up to 25% of patients with advanced cirrhosis," said Erica Villa, MD, from the University of Modena and Reggio Emilia in Italy. There are several clinical implications of PVT, including worsening of portal vein hypertension, onset of refractory ascites, increased occurrence of encephalopathy, and increased complications related to organ transplantation.
To address the issue of PVT, Dr. Villa and colleagues treated patients with advanced cirrhosis with enoxaparin 4000 IU/day subcutaneously for 1 year, followed by a second year of observation. Results from the treated group were compared with an untreated group of similar patients over the same time period.
"This study covers new ground," said Dr. Villa, "because anticoagulation therapy has never been prospectively tested for PVT prevention."
A total of 70 cirrhotic patients (Child-Pugh score of B7 to C10) were randomized in a 1:1 ratio to treatment with enoxaparin or placebo. To check for portal vein axis, patients were monitored for PVT every 3 months with ultrasound and every 6 months with computed tomography. PVT was considered relevant when it was complete or when it involved more than 50% of portal vein diameter and was symptomatic.
The study population was 50% male and a mix of cirrhotic patients with hepatitis B virus, hepatitis C virus, or alcoholic liver disease plus HCV plus nonalcoholic steatohepatitis, with a median MELD score of 13. Median age was 57 years. Patients had to be free of ascites at the time of enrollment.
At 24 months, there was a significant improvement in outcomes with enoxaparin. After 1 year of treatment, there were 6 PVT events in the placebo group (n = 36) and no events in the enoxaparin group. At the 2-year time point, there were 4 more PVT events in the placebo group and 3 events in the enoxaparin group.
"The probability of PVT was significantly higher in the untreated cases," said Dr. Villa.
"Most interesting was the occurrence of decompensation," she said. There was a significant difference in the enoxaparin group both after 1 year of treatment and at the 2-year follow-up.
There were 22 events at 1 year and 48 more at 2 years in the placebo group, compared with 4 events at 1 year and 11 events at 2 years in the enoxaparin group (P = .014). "This translates into a probability of developing decompensation of 25% at 1 year with no treatment, compared with 10% for enoxaparin, and at 2 years, 48% compared with 24% — again favoring enoxaparin," said Dr. Villa.
Not surprisingly, this reduction in events led to a significant improvement in overall survival in the enoxaparin group (P = .02), although causes of death were similar between groups. The most frequent causes of death were sepsis and liver failure. There were 4 cases of hepatocellular carcinoma reported — 3 in the enoxaparin group and 1 in the placebo group.
There were no bleeding events related to active treatment. One patient in the enoxaparin group discontinued treatment because of asymptomatic thrombocytopenia.
Results Impressive — So Far
"Patients with liver disease have low platelet counts, so they're at a high risk of bleeding already because of esophageal varicies," said transplant hepatologist Pratima Sharma, MD, from the University of Michigan in Ann Arbor. "It's that risk of bleeding that I think outweighs [the benefits of] this approach, but this is something new, and they didn't seem to see any higher risk of bleeding in their enoxaparin-treated group."
Still, for a number of reasons, Dr. Sharma doesn't think these data should guide a change in practice — not yet. "The definitions of decompensation were not very clear, and most of the patients had a Child score of 7 (30 of 34), which means someone without ascites and hepatic encephalopathy." Validation of the approach should include a broader range of patients with cirrhosis.
Dr. Villa and Dr. Sharma have disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 120. Presented November 7, 2011.
Pharmaceuticals
By PR Newswire: Biotechnology
Monday, 14 November 2011 16:11
Pipeline Update and 2011 Highlights
PSI-7977
The recently-announced registrational program for PSI-7977, the once-a-day nucleotide analog for hepatitis C virus (HCV) infection, is the first to pursue an interferon-free, all-oral regimen, and the first to include patients with all HCV genotypes (GT). The three core studies will evaluate the all-oral two-drug combination of PSI-7977 and ribavirin (RBV) administered for 12 weeks.
The first trial, FISSION, is a pivotal study of PSI-7977 with RBV for 12 weeks in approximately 500 patients with HCV GT2 or GT3. FISSION is designed to demonstrate the superiority of PSI-7977/RBV over the current standard-of-care for HCV GT2/3, pegylated interferon (Peg-IFN) and ribavirin for 24 weeks. The second Phase 3 trial, POSITRON, is planned to begin in early 2012. POSITRON will enroll approximately 225 patients with HCV GT2 or GT3 who cannot take interferon, thus supporting a placebo comparator arm for this trial. During the first quarter of 2012, data from ongoing open-label assessments of PSI-7977/RBV in subjects with HCV GT1 in ELECTRON and QUANTUM will be reviewed and incorporated into the final design for the third registrational trial, NEUTRINO. This trial will also investigate a 12-week regimen of PSI-7977/RBV versus a placebo comparator, and will enroll approximately 280 patients with HCV regardless of viral genotype, including the most common HCV genotype in the US and Europe, GT1.
At the annual meeting of the American Association for the Study of Liver Diseases (AASLD), Professor Edward Gane of New Zealand presented results from ELECTRON demonstrating viral cure (sustained viral response, SVR) in 40 of 40 (100%) patients with HCV GT2 or GT3. ELECTRON was designed to determine the minimum duration of interferon required to achieve SVR in combination with the nucleotide analog PSI-7977 and RBV. All 40 subjects were treated with PSI-7977/RBV, but were randomized to receive one of four "interferon sparing" or interferon-free regimens: 4, 8, or 12 weekly interferon injections, or no interferon. The early antiviral responses were consistent across all four experimental treatment groups with all 40 subjects achieving "undetectable" HCV RNA by week 4. Importantly, there were no treatment failures or discontinuations due to safety or viral resistance during the 12 weeks of therapy, problems that have limited the effectiveness of other direct-acting antivirals in development for HCV.
Data from PROTON, the Phase 2 dose-ranging trial for PSI-7977, were presented at AASLD by Dr. Eric Lawitz. Initial 12-week safety and on-treatment response rates had been presented in early 2011, with 98% of subjects achieving HCV below limit of detection (
At the company's investor event on November 6th, interim data from the open-label ATOMIC trial provided preliminary confirmation of the 12-week duration of PSI-7977 for all HCV genotypes, with an initial 15 of 15 subjects with HCV GT1 remaining HCV RNA "undetectable" at the SVR4 timepoint. Interferon-free assessments of PSI-7977/RBV in HCV GT1 are ongoing in ELECTRON and QUANTUM.
Collaborative Trials with PSI-7977
In the third calendar quarter, Bristol-Myers Squibb completed enrollment of a collaborative trial of 24 weeks of PSI-7977 with the BMS NS5a inhibitor, daclatasvir (with and without ribavirin) in patients with HCV GT1, GT2 or GT3. Recently, Bristol-Myers Squibb announced that four 12-week cohorts of the combination had been added in patients with HCV GT1 who: 1) are naive to prior therapy, or 2) had previously failed an HCV protease inhibitor with Peg-IFN/RBV.
In the fourth calendar quarter of 2011, Tibotec started screening patients in a collaborative study of their HCV protease inhibitor, TMC435, in combination with PSI-7977, in patients with HCV GT1 with a prior "null" response to prior Peg-IFN/RBV therapy. All subjects will be treated for 12 or 24 weeks, and will be randomized to therapies with or without ribavirin.
A collaborative study with the National Institutes of Health initiated in the third calendar quarter of 2011, evaluating 24 weeks of PSI-7977 with or without ribavirin in patients with HCV GT1
PSI-938
In September 2011, QUANTUM was initiated, a phase 2b study of Pharmasset's purine, PSI-938, administered as monotherapy and in combination with PSI-7977 (with and without ribavirin). Two treatment arms of PSI-7977 and RBV without PSI-938 are also included. All combinations will be evaluated for 12 and 24 weeks. Screening and enrollment for this open-label study have progressed quickly, and interim results from the first half of the subjects enrolled are anticipated in the second calendar quarter of 2012.
Mericitabine
Roche is currently conducting a number of phase 2 studies with mericitabine, including the INFORM-SVR study in combination with ritonavir-boosted danoprevir with and without ribavirin for 12 or 24 weeks in patients with HCV GT1. Roche recently announced an additional arm added to INFORM-SVR to assess a 24 week regimen of mericitabine, boosted danoprevir and ribavirin in HCV genotype 1 patients contraindicated for or intolerant of interferon. In June 2011, Roche initiated a second trial, MATTERHORN, to evaluate ritonavir-boosted danoprevir and ribavirin in combination with mericitabine and/or pegylated interferon. The study is expected to enroll approximately 420 subjects with HCV GT1 who failed previous therapy. Roche has stated that it intends to file mericitabine for marketing approval in 2014.
Financial Results
For the fiscal year ended September 30, 2011 Pharmasset reported revenues of $0.9 million, compared with revenues of $1.0 million for fiscal year 2010. Revenues during each fiscal year primarily consist of amortization of up-front and subsequent collaborative and license payments received from Roche previously recorded as deferred revenue.
Total costs and expenses for the fiscal year ended September 30, 2011 were $92.5 million compared to $64.7 million for the same period in 2010. The increase in operating expenses was primarily the result of increased clinical development costs associated with the initiation and ongoing conduct of the Phase 2 studies ELECTRON and ATOMIC, as well as the advancement of PSI-938 in NUCLEAR and the large Phase 2b study, QUANTUM.
Pharmasset reported a net loss of $91.2 million, or $1.25 per share for the fiscal year ended September 30, 2011, as compared to a net loss of $66.1 million, or $1.07 per share for the same period in 2010.
"In 2011, we have made significant advances with our HCV nucleotide analogs," stated Schaefer Price, President and Chief Executive Officer. "At the recent AASLD meeting we reported consistently high SVR results from PSI-7977 and ribavirin dosed with or without interferon across genotypes 1, 2 and 3. This encouraging data in combination with PSI-7977's good safety profile and high barrier to resistance have enabled us to rapidly initiate the first interferon-free phase 3 program in the industry. We are excited to pursue an interferon-free regimen in phase 3 since interferon intolerability keeps most patients from being treated for their HCV. We anticipate filing for marketing approval in the US and Europe in the second half of 2013 and hope to be the first to introduce an interferon–free regimen in the marketplace."
Calendar Year 2012 Anticipated Milestones:
| -- Initiate Phase 3 POSITRON trial with PSI-7977 and ribavirin in patients with HCV GT2 or GT3 in the first quarter of 2012 | |
| -- Report SVR24 HCV GT1 from Phase 2b PROTON study during the first quarter of 2012 | |
| -- Report interim QUANTUM data in second quarter of 2012 | |
| -- Report SVR12 from the 12-week treatment arm of ATOMIC during the second quarter of 2012. | |
| -- Report interferon-free ELECTRON data in subjects with HCV GT1 in the first half of 2012 | |
| -- Initiate NEUTRINO, an interferon free, Phase 3 study of PSI-7977 and RBV for 12 weeks in subjects with all HCV genotypes who cannot take interferon in mid 2012. | |
| -- Report SVR12 from QUANTUM in the second half of 2012 | |
| -- Report SVR12 from the arm with HCV genotype 2 or 3 subjects of Part 3 of ELECTRON during the third quarter of 2012. | |
| -- Report SVR12 from ATOMIC 24-week treatment arms during the second half of 2012. | |
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently being studied in an interferon-free, Phase 3 program (FISSION, POSITRON and NEUTRINO) and in five Phase 2b trials including subjects with all HCV genotypes. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, is in QUANTUM, a Phase 2b interferon-free trial of PSI-938 and PSI-7977 in subjects with all HCV genotypes. Mericitabine (RG7128) continues in three Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.
FDA's Off-Label Rule Under Attack
(Los Angeles Times, November 7, 2011)
"Prescription drugs and medical devices are frequently used to treat conditions other than those the Food and Drug Administration [FDA] has specifically approved them for...FDA [guidance for] doctors is to be well informed, have good scientific and medical reasons, and maintain records of any off-label use. The agency [FDA] bars…[the promotion of] products for more than their approved uses…some drug makers are...arguing [in court] that the FDA's marketing…regulations improperly 'censor' them…Off-label uses can help close the gap between the time when research demonstrates the effectiveness of a drug and the formal FDA approval. But there's a fine line between supplying information about how a product is being used off-label and promoting such a use. And the more widespread an off-label use becomes, the more it circumvents the FDA's process for ensuring that drugs and devices are safe and effective before they reach patients. Rather than loosening the restraints on marketing, policymakers should try to correct flaws in the FDA's current system that slow the spread of useful information and treatments."
Key news from the ongoing Capital Markets Day
Medivir AB (OMX: MVIR), a research-based speciality pharmaceutical company focused on infectious diseases, reports the following key news concerning their hepatitis C projects.
Medivir programmes in collaboration with Tibotec Pharmaceuticals
Medivir and Tibotec Pharmaceuticals have two programmes for the development of antiviral therapies for future treatment of hepatitis C (HCV), these are based on the HCV protease and polymerase drug targets.
In the protease project, TMC435 is in global phase III development in both treatment naïve and in patients that have relapsed after previous treatment with pegylated interferon (PegIFN) and ribavirin (RBV) in patients with chronic hepatitis C genotype 1.
The HCV polymerase collaboration program consists of two early development projects, a nucleoside and a nucleotide inhibitor.
TMC435 (NS3/4A protease inhibitor) presently in development in Hepatitis C genotype 1 infected patients.
Phase IIb studies
Final SVR24 data from the phase IIb study PILLAR, in treatment-naïve patients, was presented last week at the the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, CA, USA. Results from this final PILLAR analysis showed that TMC435 administered in combination with peginterferon α-2a and ribavirin (PR) resulted in significantly higher sustained virologic response (SVR) rates compared to placebo plus PR, with the majority of TMC435 patients able to shorten total treatment duration to 24 weeks based on response-guided therapy.
- In the 150 mg TMC435 treatment groups, 81-86 percent of patients achieved SVR24, compared to 65 percent of patients treated in the placebo arm. In addition, 86 percent of patients in the TMC435 treatment arms had a shortened treatment duration of 24 weeks, compared to a 48 weeks treatment duration for patients who received placebo plus P/R.
- The once daily dosed TMC435 was generally safe and well tolerated at all doses and treatment durations.
Medivir recently issued a press release on final results from phase IIb study ASPIRE
This trial evaluated TMC435 once daily in addition to pegylated interferon (PegIFN) and ribavirin (RBV) in patients with chronic hepatitis C whose prior treatment with PegIFN and RBV was unsuccessful either because they relapsed, had a partial response or had a null response.
- Data from the ASPIRE study showed that patients in each of these subgroups who were treated with TMC435-based combination therapy achieved superior rates of sustained virologic response (viral cure) compared to those retreated with pegylated-interferon and ribavirin alone.
- All TMC435 subgroups achieved substantially higher viral cure rates (SVR24) compared to control group (PegIFN and RBV alone): 85% vs. 37% in prior relapsers, 75% vs. 9% in prior partial responders and 51% vs. 19% in prior null responders.
o The once daily TMC435 was generally safe and well tolerated at all doses and treatment durations.
Phase III studies
SVR12 - new endpoint
- In the ongoing phase III studies in naïve and patients that have relapsed following previous treatment, the primary endpoint has been changed from SVR24 to SVR12 following recent discussions with the FDA. These studies (QUEST 1 &2 and PROMISE) were all fully recruited in August.
Phase III study in non-responder patients to be initiated
- Phase III study in prior partial and null responder HCV genotype 1 patients will start within six months. This study will evaluate efficacy, safety and tolerability for TMC435 vs telaprevir in combination with PegINFα-2a and Ribavirin in chronic Hepatitis C patients.
Phase II interferon free combination study with TMC435 and PSI-7977
- This interferon free phase II combination study will commence shortly. It will evaluate TMC435 and PSI-7977 in combination with and without ribavirin for 12 and 24 weeks in genotype 1 patients who had a prior null response to Peg-IFN/RBV. The study design is now posted on www.clinicaltrials.gov.
HCV polymerase collaboration
TMC649128
TMC649128, the first NS5B nucleoside polymerase inhibitor under the collaboration, entered into clinical development in Q1-2011. It was safe and well tolerated at all doses tested for up to 14 days.
However the antiviral activity failed to meet the target product profile and therefore the clinical development has now been discontinued.
Nucleotide program
The focus of HCV polymerase collaboration is now on a liver targeted nucleotide polymerase inhibitor program. A clinical candidate has been selected and the project is now in preclinical development stage.
Capital Markets Day Presentation
The presentation from this research & development update is available on our website under the heading Investor Relations / Latest Events.
| For more information about Medivir, please contact: | |
| Medivir (www.medivir.se) Rein Piir, EVP Corporate Affairs & IR | Mobile: +46 708 537 292 |
For more information about Medivir, please visit the Company’s website: www.medivir.com.
FYI
Milk thistle stops lung cancer in mice
Tissue with wound-like conditions allows tumors to grow and spread. In mouse lung cancer cells, treatment with silibinin, a major component of milk thistle, removed the molecular billboards that signal these wound-like conditions and so stopped the spread of these lung cancers, according to a recent study published in the journal Molecular Carcinogenesis.
Though the natural extract has been used for more than 2,000 years, mostly to treat disorders of the liver and gallbladder, this is one of the first carefully controlled and reported studies to find benefit.
Here is how it works:
Basically, in a cell there can be a chain of signals, one leading to the next, to the next, and eventually to an end product. And so if you would like to eliminate an end product, you may look to break a link in the signaling chain that leads to it. The end products COX2 and iNOS are enzymes involved with the inflammatory response to perceived wounds – both can aid tumor growth. Far upstream in the signaling chain that leads to these unwanted enzymes are STAT1 and STAT3. These transcription factors allow the blueprint of DNA to bind with proteins that continue the signal cascade, eventually leading to the production of harmful COX2 and iNOS.
Stop STAT1 and STAT3 and you break the chain that leads to COX2 and iNOS – and the growth of lung tumors along with them.
“This relatively nontoxic substance – a derivative of milk thistle, called silibinin – was able to inhibit the upstream signals that lead to the expression of COX2 and iNOS,” says Alpna Tyagi, PhD, of the University of Colorado Skaggs School of Pharmacy. Tyagi works in the lab of University of Colorado Cancer Center investigator Rajesh Agarwal, PhD.
In addition, Tyagi and collaborators compared the effects of silibinin to drugs currently in clinical trials for lung cancer. Would drugs that target other signaling pathways – other linked chains – similarly cut into the production of COX2 and iNOS?
It turned out that inhibiting the chains of JAK1/2 and MEK in combination and also inhibiting the signaling pathways of EGFR and NF-kB in combination blocked the ability of STAT1 and STAT3 to trap the energy they needed to eventually signal COX2 and iNOS production.
Compared to these multi-million dollar drugs, naturally-occurring silibinin blocked not only the expression of COX2 and iNOS, but also the migration of existing lung cancer cells.
“What we showed is that STAT1 and STAT3 may be promising therapeutic targets in the treatment of lung cancer, no matter how you target them,” Tyagi says. “And also that naturally-derived products like silibinin may be as effective as today’s best treatments.”
Analysis: Stem cell research: win some, lose some
LONDON |
LONDON (Reuters) - A decision by one of the biggest names in stem cell research to throw in the towel will not stop other pioneering work that could yet produce cures for blindness and help mend broken hearts.
Scientists were shocked by U.S. biotech company Geron Corp's decision on Monday to quit embryonic stem cell research -- a move it blamed on a lack of money and the complexities of getting regulatory approval.
Yet, at the same time, teams working with adult stem cells -- a less ambitious area -- are making good progress.
"This is not the end of an era," said Dusko Ilic, senior lecturer in stem cell science at King's College London.
Shortly before Geron told the world it was ending further development of its embryonic stem cell projects, Australia's Mesoblast Ltd reported its adult stem treatment slashed the rate of further heart problems in heart failure patients.
"It's a tale of two ends of the market. I believe the adult stem cell space was always more attractive anyway," said Navid Malik, a biotechnology analyst at Merchant Securities.
Stem cells potentially offer a new way of treating diseases for which there are currently no treatments -- including heart disease, Parkinson's and stroke -- by regenerating tissue.
Embryonic stem cells are harvested from embryos and have the potential to become almost any type of tissue. Adult stem cells are less controversial, but are also less flexible.
Like Malik, scientists agreed Geron had started in a difficult place in testing economic times.
In its most advanced project, Geron was testing an embryonic stem cell treatment aimed at helping patients with spinal cord injuries like the late Superman actor Christopher Reeves, who was paralyzed in a horse-riding accident.
"Making superman walk would have been great for business but was an ambitious target for a serious problem and maybe not the best start scientifically or clinically for stem cell therapies," said Alison Murdoch, head of the fertility center at Britain's Newcastle University.
The first patient was treated in October 2010 with Geron's product called GRNOPC1, containing cells that had been manipulated to become precursors to nerve cells.
INVESTMENT RETURN
Other research teams are focusing on eye disorders such as age-related macular degeneration (AMD) or on ways to repair damaged heart tissue -- areas where experts say progress and, crucially, return on investment is likely to be quicker.
Pfizer Inc, for example, is working with University College of London's Institute of Ophthalmology on an embryonic stem cell treatment for AMD and is now awaiting a green light to commence clinical trials in Britain.
Advanced Cell Technology (ACT) is starting early-stage human trials in the United States and Britain using embryonic stem cells in patients with a progressive form of blindness called Stargardt's macular dystrophy.
"Getting the business case right is as important as getting the science right for each stem cell therapy that we develop," said Anthony Hollander, a professor of Rheumatology and Tissue Engineering at the University of Bristol.
The ethical controversy surrounding embryonic stem cells can also have hard commercial implications, as highlighted by a ruling from Europe's top court last month that has left the business case for embryonic stem cells in limbo.
The European Court of Justice decided to ban the patenting of any stem-cell process that involves destroying a human embryo, in a move described by scientists as a major blow to the emerging field of research.
That court decision will have given pause for companies looking into embryonic stem cells but it will not affect adult stem cells derived from bone marrow, fat or skin.
"The adult stem cell space is moving forward very fast," said Malik. "We're going to see filings for regulatory approval in the next three to five years for a series of products."
Robert Lanza, chief scientific officer of ACT, is not giving up hope on the embryonic front but said Geron's exit put more pressure on his firm to succeed.
"Of course, it's the second mouse that often gets the cheese," he said.
(Additional reporting by Julie Steenhuysen in Chicago; Editing by David Cowell)
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