HCV New Drugs

From Natap

HCV Protease Inhibitor Resistance - New Monogram Resistance Assay: this report contains relevant information related to HCV telaprevir & boceprevir resistance and the new assay -
"Telaprevir-associated resistance substitutions (substitutions at positions V36, T54, R155, A156 or D168) were present at baseline in 5% (117/2239) of the subjects in the combined Phase 3 Studies. Given the small number of subjects with baseline telaprevir resistance substitutions, it is hard to make conclusions on response outcomes when these specific substitutions are present at baseline"

Immune Activation Impairs CD4 Recovery & Increases Mortality
Objectives: To assess whether T cell activation independently predicts the extent of CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART).

Patient preferences and assessment of likely adherence to hepatitis C virus treatment -
Chronic infection with the hepatitis C virus (HCV) is a common sequelae to acute HCV infection with a prevalence of 1.4% in the United States [1,2]. Currently, treatment of patients with chronic HCV infection involves the use of drugs that stimulate the immune system and drugs with antiviral activity. The unmodified interferons (alpha and beta) and pegylated interferon (alpha) are primarily immunomodulators, are given through subcutaneous injection and have side effects such as flu-like symptoms and depression. The only currently used antiviral drug, ribavirin, has a synergistic antiviral effect when combined with peginterferon [3]; it is taken orally and has side effects that can be upsetting (rash/itching) or medically serious (anaemia).

Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response
Hepatology Early View Article first published online: 24 AUG 2011"The main impact of this amendment was on the prior null responder group, where 53% completed 48 weeks of treatment. The 48-week treatment group SVR was 56% [small numbers: 15/27 (56)] "

Anadys' Setrobuvir Named One of Windhover's Top 10 Most Interesting Infectious Disease Projects to Watch
By Anadys Pharmaceuticals, Inc.
Published: Wednesday, Sep. 7, 2011 - 1:15 pm
SAN DIEGO, Sept. 7, 2011 -- /PRNewswire/ --
Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that setrobuvir (ANA598), the Company's direct-acting antiviral (DAA) currently in Phase IIb development for hepatitis C, has been selected as one of Windhover's Top 10 Most Interesting Infectious Disease Projects to Watch.

"We are honored to have setrobuvir identified as a Top 10 infectious disease project," said Kevin Eastwood, Anadys' Senior Vice President of Corporate Development. "This recognition reflects the scarcity of later-stage development assets in hepatitis C and the strong desire on the part of companies to assemble combination regimens to treat this disease. With a readout next month of the 12-week data from an ongoing Phase IIb trial, Anadys has positioned setrobuvir as a well-characterized agent, ideally suited to complement other DAAs as the treatment of HCV evolves to a DAA combination treatment paradigm."

Setrobuvir was selected by independent experts at Windhover Information and Herndon Company. The selection criteria included the breadth of business development opportunities, the current size and growth of the targeted market, and the strength of science underlying the program. Many assets selected in this manner by Windhover in prior years have been the focus of subsequent attractive business transactions.

As a selected company, Anadys will present at Windhover's 6th Annual Therapeutic Area Partnerships conference November 30-December 2, 2011 in Boston, MA. Windhover is a leading provider of business information to senior executives in the pharmaceutical, biotechnology, and medical device industries.

About setrobuvir in HCV
Setrobuvir, the Company's wholly-owned direct-acting antiviral or DAA, is an HCV RNA polymerase inhibitor that belongs to a chemical class referred to as non-nucleosides. Setrobuvir has a well-characterized safety database in which more than 350 subjects have received the agent to date. Anadys was granted U.S. Patent No. 7,939,524, which recognizes the Company's intellectual property rights to the composition of matter and methods of use for setrobuvir and related compounds. Setrobuvir has also received Fast Track Status from the FDA for the treatment of chronic hepatitis C or HCV.

Setrobuvir is currently in Phase IIb testing in combination with pegylated interferon and ribavirin for the treatment of HCV. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients complete treatment, known as SVR24. All patients are scheduled to complete their 12 week visit by the end of the third quarter of 2011 and the Company expects to release preliminary 12 week data shortly thereafter. Antiviral response data through 24 weeks are expected around year-end.
In the second quarter this year, Anadys announced a cross-company clinical trial agreement with a large, commercial-stage biopharmaceutical company to study setrobuvir in combination with another DAA in healthy volunteers.

About Anadys
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys is conducting a Phase IIb study of setrobuvir (ANA598), the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also developing ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C and plans to initiate a Phase IIa study shortly.

Safe Harbor Statement
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to Anadys' expectations regarding data timelines from the setrobuvir Phase IIb study and its belief that setrobuvir is positioned as a well-characterized agent, ideally suited to complement other DAAs as the treatment of HCV evolves to a DAA combination treatment paradigm. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements.

For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that setrobuvir or ANA773 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended June 30, 2011. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
SOURCE Anadys Pharmaceuticals, Inc.
Read more: http://www.sacbee.com/2011/09/07/3891725/anadys-setrobuvir-named-one-of.html#ixzz1XMXQyjDp

In Case You Missed It

USC scientists identify key protein linked to acute liver failure
Inhibition of protein protects liver from acetaminophen toxicity in mice
New research from the Keck School of Medicine of the University of Southern California (USC) may help prevent damage to the liver caused by drugs like acetaminophen and other stressors.
Acetaminophen, more commonly known as Tylenol, helps relieve pain and reduce fever. The over-the-counter drug is a major ingredient in many cold and flu remedies as well as prescription painkillers like Percocet and Vicodin.

However, metabolized by the liver, acetaminophen is the most common cause of drug-induced liver disease and acute liver failure in the United States and United Kingdom. Tylenol's maker announced in July that it was lowering the maximum recommended daily dosage to 3,000 milligrams to help prevent accidental overdoses.

Doctors at the Keck School of Medicine of USC have identified a protein on the mitochondria of liver cells in mice that, when silenced, protects against liver toxicity usually associated with excess doses of acetaminophen.

They found that the protein Sab, or SH3-domain binding protein 5, binds with the enzyme JNK (c-Jun N-terminal kinase). JNK regulates cellular metabolism and survival in response to stress, protecting cells when activated for brief intervals. However, JNK also kills cells when activated for prolonged periods of time.

"Because the short-term activation of JNK is associated with cell survival, Sab is potentially a better target than inhibiting JNK, which could have adverse effects," said Neil Kaplowitz, M.D., the study's lead investigator and professor of medicine at the Keck School.

Researchers have long believed that acetaminophen was converted into toxic metabolites that, in excess, overwhelm liver cells, causing them to die. In a 2008 study, Kaplowitz, who holds the Keck School's Thomas H. Brem Chair in Medicine and Veronica P. Budnick Chair in Liver Disease, and other USC colleagues turned that theory around — they found that it was not the metabolite, but rather the sustained activation of JNK that harmed the organ. By inhibiting JNK activation in mice, injury to the liver caused by large doses of acetaminophen was avoided.
In the current study, published online by the Journal of Biological Chemistry in August, the scientists silenced Sab in mice, which did not affect the metabolism of acetaminophen but successfully prevented liver injury. They also tested the effect on liver injury caused by apoptosis, or programmed cell death in response to inflammatory proteins that are implicated in many diseases and tissues — silencing Sab protected the liver in that case, too.
"We proved that the sustained activation of JNK targets Sab and is a requirement for the subsequent death of liver cells," Kaplowitz said. "We then showed that it is a universal effect. Developing a drug to protect against cell death, one could argue to target JNK — but that's a double-edged sword. This provides a whole new target: Create a drug that inhibits the interaction between JNK and Sab."
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Co-authors include Sanda Win, Tin Aung Than, Derick Han and Lydia M. Petrovic. Their research was funded by the National Institutes of Health.

Pharmasset Hep C Drug Shows Promise in Mid-Stage Trial
BANGALORE (Reuters) Sep 06 - Pharmasset Inc said its hepatitis C drug showed positive results in a mid-stage trial in patients who have not been previously treated for the infection.
In the mid-stage study, named PROTON, 98% of patients had no detectable virus in the blood 12 weeks after the treatment was completed.
Patients were given either 400 mg or 200 mg doses of the drug, PSI-7977, once daily for 12 weeks in combination with peginterferon alfa 2a and ribavirin, the current standard of care.
Patients will now be monitored to check for virus levels 24 weeks after treatment completion, which is the main goal of the study, the company said in a statement.

Progress in Hepatitis C research
Past therapies have been time-consuming and ineffective in many cases. Is this still the case?
There are different sub-types of HCV. Most people (75 percent) in the United States have genotype 1. This is more difficult to treat compared to genotype 2 or 3.
HCV treatment in early 1990s with interferon alone was ineffective. Until recently, HCV was treated with interferon and ribavirin. The cure rates varied from 40 percent to 50 percent for genotype 1. Recently, protease inhibitors were approved by the Food and Drug Administration. With the three-drug regimen, in genotype 1, the cure rate has gone up to 79 percent in those without cirrhosis and 62 percent in those with cirrhosis. The cure rate is also lower (62 percent) in African-Americans.

Are there even new therapies in the works?
Many new clinical, research trials are using three or four drugs, and some trials are being done without interferon. Early results are very promising, pushing the cure rates to almost 90 percent. New therapies without interferon are very exciting as they have fewer side effects. The progress in the last five years in this field has been very impressive.
Future trials will focus on a combination of oral medications to treat hepatitis C in a short period. Already, trials are in progress to reduce the treatment duration to three months. Trials are also being done with medication with fewer side effects.
Another area that has seen less progress is the development of effective vaccines to prevent HCV infection. Unlike HAV and HBV, there is no vaccine to prevent HCV infection.
Read More....

FDA

FDA Warns of New Infections With TNF Blockers
By Nancy Walsh, Staff Writer, MedPage TodayPublished: September 07, 2011

The Food and Drug Administration has updated the boxed warning for all tumor necrosis factor-alpha (TNFα) inhibiting drugs to reflect the risk of infection from the bacteria Legionella and Listeria.

There now have been more than 100 cases of infection with these pathogens, according to the agency.

The TNFα inhibitors licensed in the United States are infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi).
The drugs are used to treat rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and juvenile idiopathic arthritis.
Serious infections involving viral, bacterial, and mycobacterial pathogens are a recognized risk of treatment with these and other immunosuppressive drugs.

A total of 80 cases of Legionella pneumonia have been reported to the FDA among patients receiving TNFα inhibitors, most often for rheumatoid arthritis.
Median age of affected patients was 56.

Median duration of TNFα inhibitor treatment was 10.4 months, but cases occurred as early as within one month and as late as 73 months after beginning treatment.
Many of the patients were also being treated with methotrexate and corticosteroids, and 14 deaths occurred.

Thus far there also have been 23 published cases of Legionella pneumonia in patients ages 26 to 71, with three deaths.

In four of these cases, the pneumonia was severe enough to warrant mechanical ventilation, and in five cases, intensive care treatment was needed.
One patient had a second episode of Legionella pneumonia after treatment with the TNFα inhibitor was restarted.

There are also now 26 published cases of serious infections -- meningitis, endophthalmitis, bacteremia, and sepsis -- with Listeria monocytogenes in patients receiving these drugs.
Seven patients died of the infection.
In addition, FDA cautioned that Listeria infections also occurred during clinical trials of the TNFα inhibitors.

The agency continues to advise healthcare professionals to consider the benefits and risks of these drugs before initiating therapy, particularly in patients who have had chronic or recurrent infections or underlying disorders associated with immunosuppression.

Heightened risk of infection also exists for patients who are older than 65.
Any adverse events in patients receiving TNFα inhibitors should be reported to the FDA MedWatch program, the agency statement noted