Showing posts with label A-2012 EASL-AASLD Special Conference. Show all posts
Showing posts with label A-2012 EASL-AASLD Special Conference. Show all posts

Monday, October 1, 2012

New HCV drugs in development - Highlights Of The EASL-AASLD Special Conference




A special report  provided by EASL of the EASL-AASLD Conference on - Therapy of Hepatitis C: Clinical Application and Drug Development held this month in Prague, Czech Republic, is now available for viewing -  Download PDF.

Highlights Include:
 
Therapy of Hepatitis C:Clinical Application and Drug Development
HCV transmission and therapeutic intervention
One year of triple combination therapy New HCV drugs in development
Overcoming resistance and treatment failure
New ways to search for novel anti-HCV drugs
*New HCV drugs in development (provided below)
 

New HCV drugs in development

“We have come a long way with interferon treatment since it was first introduced in 1991 to the use of pegylated interferon as part of triple HCV therapy today. Some are predicting therapy will be interferon-free. But we need all the tools we can get to improve the management of HCV and novel interferons and IFN inducers may have an important role in some patient subgroups,” said Dr. Michael Manns, Medical School of Hannover, Germany.

He suggested that interferon-based therapies have several potential advantages compared to direct antiviral agents:
 
• No viral resistance
• Comparatively low cost
• Vast clinical experience
• Potential use in other viral infections such as HBV.

For the future, INF-based therapy may be appropriate for easy to treat patients, but new interferons have to be developed that are much safer and better tolerated than current options.

Newer NS3/4A protease inhibitors in combination with peg-IFN and ribavirin achieve high rates of SVR with simpler dosing schedules and generally better tolerability than older agents, according to Dr. Michael Fried, University of North Carolina, USA. He said that two years of clinical experience with the currently available PIs have shown that ribavirin is required for achieving SVR, rapid virological response is associated with highest SVR and adverse events can generally be managed but that certain populations are less responsive. New PIs in development include simeprevir and faldeprevir (phase 3) and asuneprevir and ABT- 450/r (phase 2), mostly with peg-INF + RBV backbone. Trials so far show encouragingly high rates of SVR and generally good tolerability, but we have to wait for more data, he concluded.

“It’s becoming clear that nucleoside/nucleotide analogues provide a very strong backbone for future HCV therapies,” argued Dr. David Nelson, University of Florida, USA. They work by causing premature chain termination during viral nucleic acid synthesis. The active binding site in the target – NS5B RNA-dependent RNA polymerase – is highly conserved across HCV genotypes, conferring pangenotypic activity and there is a high barrier to resistance. Three agents are currently in development: sofosbuvir (phase 3), mericitabine (phase 2) and ALS-2200 (phase 2), while some others have been put on hold due to toxicity.

“Sofosbuvir (previously GS-7977) will be the most important compound during the next 2-4 years,” predicted Professor Wedemeyer. He noted that sofosbuvir therapy was successful in various IFN-free regimens and may also help to shorten IFNa-based therapies. “However, we have learned over the last few months that there will be no ‘one-size-fits-all’ regimen with sofosbuvir.”

Non-nucleoside inhibitors of HCV RNA polymerase have no role in monotherapy and limited role in triple therapy, but they may be useful in quadruple therapy, suggested Dr. Paul Pockros, La Jolla, USA. Reviewing the available data, he noted that these agents have low to moderate potency, a low barrier to resistance and are unlikely to have crossgenotype activity. “Of the 13 non-nucleoside inhibitors in development in 2008, a lot have given disappointing results, with only six remaining,” he said. Of these, Vx-222 is the most potent, achieving a 3.4 log10 reduction in viral load (at a dose of 400mg bid) and is currently in phase 2. However, some compounds may still be used in IFN-free treatment regimens if combined with other highly potent DAAs.

Therapeutic vaccines represent a scientifically valid approach to treating HCV but there is a long way to go to optimise vaccine response, suggested Professor Heiner Wedemeyer. He questioned whether vaccines for HCV are needed at all, with all the new drugs currently in development, but suggested several reasons why they may be useful. “First, HCV is not HIV,” he pointed out. “Immune control of HCV is possible, in contrast to HIV infection.” Clinical observations show – quite remarkably – that 10-50% of cases of acute hepatitis C are cleared without treating, suggesting a major role for the immune system.

Combinations including NS5A inhibitors appear likely to address many of the current unmet medical needs in HCV, especially for patients who remain difficult to treat with currently available therapies, including those with cirrhosis and patients undergoing liver transplant, according to Dr. Stanislas Pol, Hopital Cochin, France. Reviewing the data with daclatasovir, the first agent in the class, he said it is very potent, has broad genotypic coverage and has a pharmacokinetic profile supportive of once daily dosing, making it easy to take. A recent study with quadruple therapy including daclatasovir, asapravir and peg-interferon/ ribavirin has shown ‘fantastic results,’ he said, with SVR4 of 90-100% in a difficult to treat group of genotype 1 null responders. Moreover, NS5A inhibitors are part of many IFN-free treatment regimens.

Cyclophilin inhibitors offer the benefits of a high barrier to resistance and no cross-resistance with protease or polymerase inhibitors, Professor Robert Flisiak, Medical University of Bialystok, Poland, told the meeting. They act on NS5A, NS5B and NS2 HCV viral proteins, as well as preventing HCV-mediated mitochondrial and endogenous interferon production.

Alisporivir – the most advanced agent in the class – has shown effects in treatment na├»ve, previous non-responders and in HIV/HCV coinfected patients. It has demonstrated antiviral efficacy against the four most prevalent genotypes (1,2,3 and 4). It is effective in interferon-free regimens, as well as providing additional antiviral effects in combination with peg-interferon plus ribavirin, and is well tolerated. However, it is currently on hold due to toxicity in combination with PEG-IFNa. Future trials may therefore focus on IFN-free regimens including alisporivir.

Entry inhibitors, which block the entry of HCV into cells, are at an early stage of development but proof of the concept has been demonstrated in cell culture and in vivo models, reported Professor Thomas Baumert, University of Strasbourg, France. They are pangenotypic, prevent infection with escape variants and provide a complementary mechanism of action of direct antiviral agents, demonstrating marked synergy. “They offer a very attractive antiviral strategy for the prevention of liver graft infection in patients who have undergone transplantation, as well as for difficult to treat patients and those with multiresistance,” he suggested.

Thursday, June 28, 2012

EASL-AASLD Special Conference on Therapy of Hepatitis C

European Association for the Study of the Liver

EASL-AASLD Special Conference on Therapy of Hepatitis C
Clinical application and drug development


The European Association for the Study of the Liver (EASL), together with the American Association for the Study of Liver Diseases (AASLD), will be holding an exciting "Special Conference" dedicated to the timely topic of:

Therapy of Hepatitis C: Clinical Application and Drug Development
During the three days of the conference – held from 14-16 September 2012 in Prague, Czech Republic - leading international Hepatitis C experts will highlight and address a series of lectures, and participate in interactive debates on hop topics in Hepatitis C. Case presentations and parallel interactive sessions will take place and space will be reserved for poster presentations of original works in the field.

The EASL-AASLD Special Conference provides an opportunity to keep abreast of the latest developments in this rapidly advancing field. The programme has been designed to provide adequate time for discussion and networking and will address a variety of areas including:

  • Global scale intervention and control of HCV
  • Prospects for a preventive HCV vaccine
  • Review of new drug treatments in development such as Nonnucleoside inhibitors of HCV RNA polymerase, NS5A inhibitors, and Cyclophylin inhibitors
  • Effectiveness of triple combinations in cirrhotics

Prof. Dr. Heiner Wedemeyer, a former EASL Secretary General and one of the Special Conference organisers, said a major discussion point at the conference will deal with the real-world use of new direct-acting antivirals (DAAs):

"We will discuss how to manage the side-effects of DDAs in real-world settings, and also their efficacy in populations not treated in pivotal registration trials. This is extremely important for physicians who are starting to use the drugs, particularly in terms of which patients should now be treated," said Prof. Dr. Heiner Wedemeyer.

Moreover, Prof. Dr. Wedemeyer said perspectives on Interferon (IFN) free treatment regimens will be extremely exciting: "After more than 25 years, we can now develop therapies that will not require IFN-alpha, which causes many side-effects and is also very expensive. We are experiencing a paradigm shift in the therapy of hepatitis C. This conference will also be very important for the development of new guidelines in Europe!"