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Curing HCV For Many Coming
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There has been a lot of attention paid to this published study this week in the New England Jnl of Medicine, and rightfully so. It reports results that were however presented last April in 2011 at EASL, the European annual liver conference. The results of this study caused a landshift in HCV treatment, this study was the very first to find you could cure HCV without peginterferon+ribavirin. Before this study we thought perhaps we could do this, cure HCV without peg/rbv, but there was no data to support this yet. So the study investigators and BMS who developed the 2 oral HCV drugs used in the study gave 2 oral HCV drugs, an experimental NS5A inhibitor & an experimental HCV protease inhibitor only, no other HCV drugs, to the most difficult to treat patients: null responders, genotype 1 patients, patients that did not respond to previous peginterferon+ribavirin treatment. The only previous options for such patients was to be retreated again with peg/rbv and these studies found 10% response rates, very poor. This new study, granted only in 11 patients, found 36% 4/10 patients were cured with only the 2 new oral HCV drugs. Very interestingly 11 different patients in this study received 4 drugs, these 2 new oral HCV drugs plus peg/rbv and all 11 were cured. THIS STUDY PROVIDED PROOF-OF-CONCEPT that we can cure HCV+ patients without peg/rbv. Since this study was presented last April it has led to many researchers & drug companies to conduct studies to duplicate the same results in larger numbers of patients so we can fully characterize that we can eliminate peginterferon and ribavirin from therapy & to find the exact regimens that will accomplish this. Also companies are conducting studies trying to eliminate first peginterferon but keeping ribavirin in regimens, with excellent results. Multiple studies find that combining ribavirin with new oral HCV therapies but without peginterferon is very effective. So we will see in the near future regimens with 1 or 2 or maybe 3 new HCV drugs in combination with ribavirin, with I expect very high cure rates. At AASLD, the annual liver meeting in Nov 2011 Pharmasset reported in relatively small numbers of treatment-naive genotype 2/3 patients they cured 100% of patients with only 2 HCV dugs, their nucleotide PSI-7977 plus ribavirin, and after that conference Gilead bought Pharmasset for $11 Billion so they could have that drug PSI-7977 and so Gilead is developing therapies & treatment regimens including PSI-7977, and Gilead had already been developing their own additional HCV drugs in other classes including protease, NS5A & NNRTIs. BMS at the same time early last year started a study that included some treatment-naive genotype 1 patients receiving only 2 new experimental HCV drugs PSI-7977 plus their own NS5A inhibitor, results are expected soon, good results are anticipated. PSI-7977 is expected to begin phase 3 studies within months conducted now by Gilead, with an expected timeline of at most 2 years to get to the pharmacy unless this is expedited approval process by the FDA if results are very good, which I think is a possibility, there is precedence for accelerated approval. At the same time Tibotec started their own study with only 2 HCV drugs which includes again PSI-7977 plus the Tibotec HCV protease inhibitor and we are waiting for results. Last April 2011 Pharmasset reported results from a small study giving genotype 1 patients only 2 new experimental HCV drugs PSI-7977 and PSI-938, which is the other nucleotide they were developing and 95% cure rates were achieved without peg/rbv in genotype 1 patients. Some of the new drugs work only in genotype 1 patients but some of the new drugs are what is called pan-genotypic meaning they are effective for all genotypes 1 through 6. Since, very recently, news came out that PSI-938 was found to have a toxicity so the drug was put on hold but PSI-7977 continues on without any toxicities, and no toxicities have been seen in any other nucleotides. PSI-7977 is a nucleotide which is considered an important new class of HCV drugs because it is potent, once-daily administration, appears clean/few side effects and does not develop drug resistance at all so far. SO, a small biotech Inhibitex has developed INX189, a nucleotide that is in earlier development but was reported at AASLD in Nov 2011 to look as potent in studies in patients as PSI-7977, so BMS bought this company & this drug for $2.5 billion. At the same time, early in 2011 Vertex bought 2 nucleotides from a small biotech company called Alios. They have feverishly started new studies in late 2011 to examine & establish as quickly as possible the safety & potency of these drugs, with early results expected in early 2012, and of course with positive/encouraging results Vertex will very quickly develop & study these 2 nucleotides in studies in patients with perhaps a 2 year timeline for extensive data. Also currently in phase 3 are 2 new HCV protease inhibitors. As you know 2 brand new HCV protease inhibitors were approved by the FDA in the Summer of 2011, boceprevir (Victrellis) from Merck & telaprevir (Incivek) from Vertex. One of these 2 protease inhibitors plus peg/rbv increases cure rates to about 79% from the old standard of care of 40-45% in genotype 1 patients. Studies with telaprevir showed 79% SVR/cure rates, studies with boceprevir showed 69%% SVR/cure rates. These protease inhibitors are taken 3 times daily. Side effects associated with telaprevir include the possibility of skin rash & anemia & potential side effects associated with boceprevir is anemia. Currently in phase 3 are 2 new HCV protease inhibitors, the Boerhinger Ingelheim protease & the Tibotec HCV protease. Both are taken once daily. Also in phase 3 right now is a cyclophillin inhibitor, a new class of HCV drugs, called allisporivir, from Novartis. This drug appears to be potent as well. These 3 new drugs currently in phase 3 are expected in about 2 years to be in the pharmacy. Also, BMS is developing a potent, first-in-class NS5A inhibitor, as mentioned above. This drug is about to enter phase 3 if it hasn't already, and also is expected to become available in 2 years. In sum we have 2 new protease inhibitors now in the pharmacy & in 2 years expect 2 additional new protease inhibitors, and the nucleotide PSI7977 & the cyclophillin inhibitor allisporivir. PSI-7977 is likely to be able to be combined with a protease inhibitor but you cannot combine 2 protease inhibitors in the same regimen. The possibility of combining the cyclophillin inhibitor plus a protease inhibitor will be studied, I think we will be able to combine allisporivir with the nucleotide PSI7977 but of course that will have to be studied & confirmed. At the same time Abbott and Roche/Genentech are developing several of their new HCV drugs. Abbott has a potent HCV protease, 2 NNRTIs, and a NS5A inhibitor in studies in patients. Roche/Geentech has a potent HCV protease, a nucleoside, and a NNRTI in studies in patients. Both Abbott & Roche/Genentech are expected to report new study results soon at the EASL liver meeting in Barcelona this April, where we can also expect lots of new exciting study results from all these new drugs including peginterferon-sparing treatment and treatment regimens that include ribavirin but without peginterferon. There are several small biotech companies also developing drugs including Idenix, Achillion & Presidio, all of whom have interesting & promising HCV drugs. Achillion has 1st & 2nd generation NS5A inhibitors & protease inhibitors. Presidio has several promising NS5A inhibitors. Idenix has IDX1984 a nucleotide that appears to be less potent than these other nucleotides, and also has a protease & a NS5A. There are anywhere from 4 million to I estimate perhaps 8 million in the USA with HCV and an estimated 170 million globally with HCV-infection, but only 1 million have been tested & diagnosed in the USA and much less having been treated. So there is a gigantic undiagnosed patient pool in the USA & globally. It will however take tremendous resources/funds to provide adequate testing opportunities in the USA & of course globally. So far the US Federal government has provided next to nothing to conduct HCV testing in the USA. A small testing project funded by the NIH is expected to be announced in 2012 but it is likely to be too small to have adequate impact in diagnosing all the HCV+ patients in the USA, not to mention globally. We will I expect be able to cure close to 100% of treatable patients when the many the new drugs begin to become available in several years when we can put together various regimens comprised of 2, 3 or 4 oral drugs with or without peg/rbv. Another consideration is the aging-out of the HCV+ patient population. A large proportion of people with HCV were infected in the 1950s & 1960 and so are now in their 50s & 60s of age. It can take as long as 20-30 years for serious disease progression in many patients. So now serious liver disease is beginning to be reported in many aging patients, which means that unless diagnosed & treated these older patients with advanced liver disease are at great risk for serious disease complications & death. We need awareness campaigns & testing programs to identify & provide care for these patients. In addition there is a severe shortage of well trained clinicians who could take care of all these undiagnosed patients. we don't right now have enough clinicians to provide the care for so many patients. We need to be able to train new clinicians. Unlike in HIV where we have the $1 billion Ryan White Care Act which provides care & services for HIV+ individuals, there is no such program for HCV. This Care Act also supports funding for clinics where patients can receive care, and is particularly crucial for poor patients & marginalized patient populations. This program also provides free HIV drugs to uninsured patients. HCV Care & treatment is a difficult process for patients, who need care, treatment & support services including case management & crucial support services. Many HCV+ individuals are from severely marginalized patient populations including former & current IDUs, individuals receiving methadone maintenance. Some of these individuals need additional support services & special care. Conducting studies & providing special care clinics would be very important in providing adequate care for many of these patients. But again there so far is very little of this & funding from the Federal, State & City governments to provide such programs is basically totally absent. In sum, we will be able to cure close to 100% of HCV-infected treatable patients but we need funding & programs to better prepare to address the needs of many marginalized patient populations. Jules Levin
First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published - BMS press release - (01/19/12)
Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1: 'this was the proof-of-concept study showing SVR ('cured') could be achieved without peg/rbv & with only 2 new oral HCV drugs' - (01/19/12)
The end of the beginning for hepatitis C treatment - (01/13/12) Commentary
The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C - (01/13/12)
Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders - (01/13/12)
Cost-effectiveness of hepatitis C virus antiviral treatment for injection drug user populations - (01/12/12)
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