Dramatic Changes in Hepatitis C Treatment Expected to Continue


Xconomy San Diego — 

Earlier this year the FDA approved telaprevir (Incivek) from Vertex Pharmaceuticals and boceprevir (Victrelis) from Merck for the treatment of hepatitis C. Both agents are protease inhibitors and represent the first approvals of direct acting antivirals for hepatitis C. Direct acting antivirals are a broad class of agents that act to block the growth of viruses by directly disrupting essential viral functions. The benefit of these drugs for hepatitis C follows the dramatic success of this class over the last 15 years in HIV. Now the future advances of direct acting antiviral therapy for hepatitis C is expected to follow a central theme of their use in HIV: that combination of multiple antivirals in a single treatment regimen will provide greater benefit than use of any one antiviral drug alone.

The new protease inhibitors were approved for use only in combination with two previously approved agents, pegylated interferon and ribavirin. The addition of either protease inhibitor increased clinical cure rates, known formally as sustained viral response (SVR) rates, by 30 to 40 percentage points over control groups receiving the standard pegylated interferon and ribavirin alone. As dramatic as these improvements are, there is a good chance for even more dramatic improvements if all-oral regimens, assembled by combining multiple direct acting antivirals, are able to maintain high cure rates while eliminating injectable interferon and its associated flu-like side effects that patients have long sought to avoid.

Next in the development queue are three agents that entered Phase III development this year, including two additional protease inhibitors (TMC435 from Johnson & Johnson’s Tibotec unit and BI201335 from Boehringer Ingelheim) and a cyclophilin inhibitor that disrupts a host function required for viral replication (alisporivir from Novartis). All three Phase III programs are exploring a modality similar to the approved agents, i.e. addition of a single new agent to the standard pegylated interferon/ribavirin. The ongoing Phase III programs will hope to demonstrate one or more advantage over the recently approved agents, potentially including better tolerability, further increases in cure rates, shorter duration of therapy and/or an increased proportion of patients successfully treated with shortened therapy. While such improvements may well be achieved, they may become less important or even irrelevant if the rapidly expanding number of direct acting antiviral combination trials leads to identification of new regimens that surpass all regimens that are based on a single antiviral drug added to the old standard regimen.

Investigation of direct acting antiviral combination regimens has exploded in the last 12 months. This advance has become possible because of the diversity of antiviral mechanisms distinct from protease inhibitors that are now represented in the pipeline of hepatitis C drugs in Phase II development across the industry. Diverse mechanisms are important because they typically provide distinct resistance profiles, and antiviral combinations are being assembled using new compounds with non-overlapping resistance profiles to provide a greater barrier to the development of antiviral resistance. Additional factors that are considered important in assembling optimal combinations include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles and a low potential for unfavorable drug-drug interactions. The more extensively characterized each individual antiviral drug is, the lower the risk of an unanticipated negative interaction between the drugs once combined.

New mechanisms other than protease inhibitors that have entered large Phase IIb studies include non-nucleoside polymerase inhibitors (setrobuvir from my company, Anadys Pharmaceuticals, as well as tegobuvir from Gilead Sciences and filibuvir from Pfizer). Another class is composed of nucleoside/tide polymerase inhibitors (mericitabine from Roche and PSI-7997 from Pharmasset). There’s also an NS5a inhibitor in Phase IIb development (BMS-790052 from Bristol-Myers Squibb).

At Anadys, we chose to focus on the non-nucleoside class of polymerase inhibitors for several reasons. We recognized an inherent potential for an excellent safety profile, given the absence of structurally related host targets and the ability to generate inhibitors without relying on close analogs of host metabolites. The excellent safety record to date for setrobuvir is consistent with our initial expectations regarding safety. The diversity of applicable chemotypes also led us to expect a clear path to patent-protected intellectual property, exemplified by our recently issued U.S. patent covering setrobuvir. In other antiviral drug classes, especially nucleosides/tides and NS5a inhibitors, the range of useful chemical space discovered to date is considerably more narrow, leading to the potential for more interference on the IP side. Lastly, we recognized that a potential liability of the non-nucleoside class, a lower genetic barrier to resistance, could likely be addressed if we were able to engineer a high pharmacological barrier to resistance into candidate molecules. This recognition was based on the lessons learned about non-nucleosides in the 1990s in HIV. Specifically, there were two disappointing product introductions of non-nucleoside products for HIV that were plagued with rapid emergence of resistance—nevirapine (Viramune) from Boehinger Ingelheim and delavirdine (Rescriptor), now marketed by Pfizer. After that came efavirenz (Sustiva) from Bristol-Myers Squibb, so named for its ability to last longer in the bloodstream, which demonstrated that a non-nucleoside with good potency and a prolonged plasma half-life could demonstrate a dramatically improved resistance profile. While we reasoned that a similar solution would be applicable in hepatitis C, we also understood the significant medicinal chemistry challenge to accomplish this objective and furthermore understood that the technology platform at Anadys was exquisitely well matched to the molecular engineering challenge of simultaneously optimizing potency and pharmacokinetics. The excellent resistance profile of setrobuvir observed to date demonstrates the high pharmacological resistance barrier achieved with setrobuvir, and data to date is consistent with our idea that a high pharmacological barrier to resistance could serve in place of a high genetic barrier to resistance.

As the hepatitis C development landscape continues to advance, we expect to see an increasing number of direct acting antiviral combination trials and subsequent approval of new agents based on data derived from such trials. The FDA as well as patient advocacy groups have been strong proponents of investigating antiviral drug combinations prior to approval of individual components, and I expect an ongoing favorable regulatory environment towards combination trials provided that each individual agent is sufficiently well-characterized.

Companies that believe in the importance of antiviral combinations for future commercial relevance in hepatitis C are likely to have opinions as to how many drugs they believe will be needed in antiviral combination regimens, and are likely to pursue strategies directed at accessing at least that number of compounds if not a greater number as insurance against attrition. Mathematical modeling from Perelson and colleagues suggests that interferon-free regimens will need to contain three or four distinct antiviral mechanisms to result in viral eradication (SVR) prior to emergence of resistance. To access the required number of drugs, companies have several business alternatives available. They can rely on maturation of their internal pipelines, although few if any companies appear today to have sufficiently robust internal pipelines to rely exclusively on this approach. Companies can rely on cross-company clinical collaboration agreements to gain initial data on particular antiviral combinations, although this approach doesn’t directly answer the question of how to seek approval and launch effective marketing efforts for the individual components studied in a cross-company antiviral drug combination trial. Companies with antiviral drugs other than protease inhibitors can look to utilize one of the approved protease inhibitors as one other mechanism, analogous to the use of interferon and ribavirin in the development of the protease inhibitors to date, but this will only be a partial solution if three or more DAAs are required. Lastly, companies can gain exclusive access to antiviral drugs outside their current pipelines through a variety of business deals, allowing them to quickly assemble a pipeline with sufficient depth to increase the chances of being early to market with a successful combination regimen. To date, examples of all these strategies except combination with one of the approved protease inhibitors have been pursued by one or more companies. Going forward, these efforts across the industry are likely to culminate in approval of direct acting antiviral combination regimens, with the ultimate goal of assembling combinations powerful enough to eliminate interferon and perhaps ribavirin from hepatitis C therapy. These advancements may occur within the next few years, and if realized, would represent yet another dramatic improvement in hepatitis C therapy, at least as dramatic as the advances recently realized with the approval of the first protease inhibitors.

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22 responses to “Dramatic Changes in Hepatitis C Treatment Expected to Continue”

  1. Jim Wilson says:

    When will post transplant patient populations be included in clinical trials of HCV agents? Current new drugs interfere with Tacrilimus levels causing potentially toxic increased levels and potential kidney damage. This area represents a significant patient population yet companies seem to avoid.

  2. Talat Mehmood says:

    I hope that all the efforts made to treat Hepatitis C will be succesful.we will pray to achive the goal.may God help u.mail me further developments.

  3. Jeffrey Fried says:

    And what about those of us for whom combination therapies with interferon is not an option? When will these companies provide a non-interferon based solution?

  4. suzan krieger says:

    Hepatitis C genotype 2 –failed on riberviran and interferon due to hemoglobin reaction. will there be something for me?

  5. Mike Murphy says:

    I’d like to echo the observations of Jim Wilson – when will a post-transplant regimen be available to this population? I’ve tried the interferon/ribavirin programs twice without achieving SRV. It’s like living with a time bomb.

  6. Suzan says:

    When will the treatment for hepatitis c genotype 4 be availble for non responders and above 60 years old? Please email me the answer.

  7. taz says:

    I so hope that they get meds for all geno types & all of us with hep c!! i am a non responder & will get to try the incivik for two weeks. if i respond weel, then i get to stay on it, if not i get off it.. it seems to hurt u in being resistant to any possible new drugs? is the way i understand it! weird.. i did the SOC twice for 3 months. didn’t work. wish i had not done it the second time.. God be with us & the scientists who are working hard to discover new meds..

  8. onindo says:

    can i drink bear after taking the hepatites c treatment?

  9. Edward says:

    Trials for genotype 4?

  10. alfred says:

    How do herbal medicines ( such as Sho-Saiko-to, recently studied at Sloan Kettering ) compare. There results seem at least as good.

  11. Gabriel says:

    I’ve been on Victrelis for 4 months and the virus is starting to climb again after going from 2.3 million to 1196 in 7 weeks.
    I gave blood to see if there are Protease Inhibitor mutations. If there are, we stop treatment. If not and the viral load is still climbing, the doctor is considering switching me over to Incivek. Anybody have any thoughts on this switching?

  12. Susan Cosco says:

    I think that some of these trials should be allowing Protease Inhibitor -failure patients. If a company could proof that their drug could clear the virus in a patient who had failed treatment using Pegasys+Incivek (I was exposed to these 2 drugs in trial, but was randomized into the no Riba group), then, it would definitely show that their drug was a superior drug in this subset of patients. I happen to know of several protease inhib. (Hep C) patients, who failed this drug therapy.

  13. Ben says:

    How does one acquire such break through treatment with out insurance?

  14. wendy says:

    Please develop a non interferon treatment that can be tolerated well and effective for all genotypes!

  15. Jeff says:

    I took pegylated interferon and ribavirin for 11 months in 2003-2004 but the virus was detected again 6 months after completing the treatments. In July 2011, I began the same treatment with the new Victrelis. On October 31, 2011, I was found on the floor foaming at the mouth and was rushed to the ER. I spent 9 days in ICU with Pneumonia and Pulmonary Edema. I was told it wasn’t due to the meds but when asked if it could have caused my immune system to allow it, I didn’t get a straight answer. Could it have contributed? I was told I had several seizures for a few days and doctors told me that initially they thought if I survived, I would have a good chance of having brain damage. I think I have a good doctor but I don’t feel he keeps me advised on my condition. I was taken off the treatments while I was in ICU and I don’t see my doctor again for 6 months (July 2012). I am so confused, I don’t know what to do or expect and have no family. May God help us all to make the correct decisions and get well with minimal side effects ASAP.

  16. c.hemsley says:

    Im hcv genotype 1 ive had first lot of standard tx and was a non responder now been asked to participate in clinical trials. But after being on peginterferon/ribvarin and treatment was stopped after 12wks no virological response of 2 logs or more, also low platelets and white cell count would i still not encounter the same issues with the newer drugs or maybe not any advice would be great.The liver specialist said either the clinical trials would be at barts or cambridge hospital in the uk.Thanks Colin.

  17. Bill Pomeroy says:

    I have end-stage liver disease caused by Hep C. Transplant is only option. Has this drug been tested on patients pre-transplant and/or post-transplant?

  18. Sharon says:

    I am Genotype 1b and have had Hep C for approx 37 years.  I started the newly approved “triple treatment” (pegylated interferon, ribavirin and  telaprevir (Incivek)) Oct, 2011 and completed treatment April, 2012.  The bad news – the first 12 weeks on Incivek almost killed me it was so difficult.  The good news – I went viral load “undectable” at week 2 and have stayed that way throughout and after the treatment.  In Oct I will know for sure if I cleared the virus.  The downside was the treatment – the UP side is I feel better then I have in years.  I am so glad they continue to develop new treatments for this difficult disease.  I wish you all the best. 

    • Nola says:

      My husband is going to start the same treatment with the same Genotype.  The first interferon/ribavirin treatment did not work.  He said he knew it didn’t prior to the six months due to how his body felt.  May your body continue to feel great and in October you receive the results of “non detectable”. 

  19. bruce says:

    have you herd of bht for treatment