Don't Delay HCV Therapy Too Long Hepatitis C treatment an ordeal worth enduring 3/12/2007 7:36:46 AM Tribune Media Services  DEAR MAYO CLINIC: I am a 55-year-old male diagnosed with hepatitis C virus (genotype 1) in 1994. Liver biopsies in 1996 and 1999 showed mild inflammation. Now, a biopsy shows progression to grade-2 chronic hepatitis with stage-2 fibrosis, and I am deeply concerned about this. I have heard about interferon treatment with ribavirin, but am concerned about side effects. What other options may be available in the near future, and will any have fewer side effects? Of the six known hepatitis viruses, hepatitis B and C are responsible for the great majority of persistent infections that result in inflammation and scarring of the liver, thereby compromising its function. Over time, usually decades, hepatitis C virus (HCV) infection can lead to cirrhosis (widespread scarring of liver tissue), liver failure or liver cancer. The virus is primarily transmitted by means of contaminated blood -- through blood transfusions, for example, or needles shared by drug users. People with HCV may experience symptoms such as fatigue, nausea, low-grade fever and persistent or recurring yellowing of the skin and eyes (jaundice). Many patients with HCV infection, however, report few or no symptoms. This virus tends to do its nasty work in silence; it can damage the liver, sometimes extensively, even in the absence of symptoms. If routine tests show only slight liver abnormalities, some doctors may decide against medical treatment at that point because the patient's long-term risk of developing a serious disease is slight. But given the details you provide in your question, now is a good time for you to consider treatment. Grade 2 and stage 2 respectively indicate significant, though moderate, amounts of liver-tissue inflammation and fibrosis (scar formation), both of which are measured on a scale of 0 to 4. Progression is no longer mild enough to ignore, and the benefits of treatment outweigh the risks -- it could reduce or prevent any further damage. The standard of care for hepatitis C treatment is indeed interferon combined with ribavirin (Rebetol). Interferon (brand name: Peg-Intron or Pegasys) is a protein that stimulates the immune system to attack invaders such as HCV. Although ribavirin doesn't appear to have antiviral properties against hepatitis C when used alone, in combination with interferon it acts to prevent the HCV infection from returning once it has been cleared by the interferon. Most patients have reasonably good prospects with this combination therapy, and in many cases it causes the virus to disappear altogether. HCV has six main "genotypes," or variants. Among genotype 1 patients, therapy will eliminate the virus some 40 percent to 50 percent of the time, and even more often -- 75 percent to 80 percent -- in genotype 2 or 3 patients. But as you note, there is a price to pay. Interferon side effects almost always include flu symptoms (which occur because the immune system has been stimulated) and may also include diarrhea, weight loss, reduced white blood cell and platelet counts, irritability, depression, insomnia, and problems with concentration and memory. Ribavirin can cause a low red blood cell count and gout. Both drugs can lead to skin irritation and extreme fatigue. Moreover, genotype 1 patients usually require higher drug doses and a longer course than do "non-1" patients. Although side effects can be quite unpleasant in some cases, other patients hardly notice any. Either way, there are medications and strategies for substantially reducing virtually all of these effects. Only about 7 percent of HCV patients undergoing combination therapy need to stop it. Other medications are in the pipeline. Two classes in particular -- protease inhibitors and polymerase inhibitors -- show particular clinical promise. One drug in each class is currently in Phase III trials (with human patients) and, if successful, could be approved by the FDA in about two years. Both of these drugs, as well as others under development, will likely be used in combination with interferon too, though possibly at lower doses and for shorter duration. -- Dr. Michael R. Charlton, Gastroenterology, Mayo Clinic, Rochester. VX-950 12 Weeks at EASL in April VX-950 is the first oral HCV drug in the development race to the market, a race containing numerous oral drugs from many drug companies. There are a handful of HCV protease inhibitors, of which VX950 is one. And there are numerous polymerase inhibitors. If the VX950 program goes without a hitch or delay the drug may be on the market in 2009. PegIFN and ribavirin will be part of the regimen. In April at EASL, the annual European liver conference taking place this year in Barcelona, Vertex will present results of patients taking VX950 after 12 weeks from an ongoing study. At EASL there will be reports on several new HCV drugs in development & I will be at EASL reporting to NATAP readers about the new information. The ongoing VX950 study has 4 treatment arms which include VX950+pegIFN+RBV for 12, 24, and 48 weeks. Here is a link to a report reviewing the study design: Vertex Pharmaceuticals Initiates the First of Two Major Phase II ... The PROVE 1 and PROVE 2 studies have been designed as major, complementary studies to be conducted in the United States and Europe that will evaluate the ... http://www.natap.org/2006/HCV/052306_01.htm Vertex Shareholders Stay Vexed By Adam Feuerstein Senior Writer 3/21/2007 7:57 AM EDT URL: http://www.thestreet.com/newsanalysis/biotech/10345652.html New clinical data from Vertex Pharmaceuticals (VRTX) regarding its hepatitis C drug telaprevir, expected at a medical meeting next month, seem to have investors on edge. Shares of the Cambridge, Mass.-based biotech firm continue show weakness on worries that telaprevir won't live up to expectations when new phase II data are presented at the European Association for the Study of Liver Disease meeting on April 11-15. I last wrote about telaprevir in early February with Vertex shares at $35, at the time down from a recent high of $44. On Tuesday, the stock closed up 20 cents at $27.85. Like then, there doesn't seem to be a specific nugget of negative information about telaprevir forcing Vertex lower (at least not that I've been able to pick up). Instead, there's a general uneasiness -- even confusion -- about the telaprevir data that Vertex will bring to the EASL meeting and how it will be interpreted by hepatitis C experts and investors. At the risk of coming off a bit too wonky, I want to preview Vertex's upcoming EASL presentation. It may not dispel any fears, but with any hope it will make interpreting next month's data easier. The most highly anticipated news will come from what is known as "Arm D" of Vertex's Prove 1 study. In this arm, 20 treatment-naive hepatitis C patients (those who have never taken anti-hepatitis C drugs) were given a triple combination of telaprevir plus interferon alpha and ribavirin (the latter two drugs representing the current, standard hepatitis C treatment.) Patients in this arm of the study were treated with all three drugs for 12 weeks, then all treatment was stopped. Twelve weeks after stopping treatment, patients are being analyzed to see whether the hepatitis C virus in their system remains at undetectable levels. In hepatitis C circles, this is what's known as a "sustained virologic response," or SVR. Since SVR, in this case, is being measured 12 weeks after treatment ends, the data that Vertex will share at the EASL meeting will be SVR12 (from Arm D of the Prove 1 trial, to be exact.) "This will be the first time in a clinical trial that any [hepatitis C] infected patient will have systematically been stopped at 12 weeks to see whether or not they can achieve SVR or not," explained Vertex's Chief Medical Officer John Alam at an investor conference last week. What makes these data so intriguing is that they represent Vertex's home-run strategy with regard to telaprevir, because 12 weeks on a drug would be the shortest treatment ever conceived for hepatitis C patients. Currently, hep C patients, like those enrolled in Prove 1, need to be treated for 48 weeks with interferon and ribavirin before they can be cured. Naturally, an aggressive stab at a 12-week treatment schedule is a risky strategy for Vertex, so the other arms of the study are exploring different treatment regimens: all dose telaprevir for 12 weeks like in Arm D, but they also extend interferon-ribavirin treatment for longer periods. Believe it or not, that's the easy part of understanding the upcoming data. Now, we get to the complexities. If all 20 patients in Arm D of the study were to make it through 12 weeks of treatment and 12 weeks of observation, interpreting the SVR12 data would be relatively easy. We'd just take the number of patients with undetectable virus and divide by 20 to come up with an answer. Unfortunately, it's very possible (and probably likely) that not all 20 patients in Arm D make it through 12 weeks of treatment. (And remember, these patients are getting telaprevir, interferon alpha and ribavirin.) According to criteria built into the Prove 1 study design, Arm D patients have to achieve undetectable levels of virus at four weeks and 10 weeks of treatment in order to stop treatment altogether at 12 weeks. If a patient doesn't meet this interim efficacy hurdle, doctors will order patients to continue receiving interferon and ribavirin for an extended period beyond 12 weeks. Since these "nonresponding" patients will still be receiving treatment for their hepatitis C, Vertex won't be able to analyze them for SVR12 response. The denominator for the Arm D analysis, therefore, will be something less than 20 patients. And this is where investors will have to pay close attention to how Vertex reports the data. Here's why: Let's assume that Vertex tells us that 13 patients in Arm D achieved an SVR 12 weeks after stopping treatment with telaprevir, interferon and ribavirin. Furthermore, Vertex tells us that four patients were deemed "nonresponders" and are therefore still being treated with interferon-ribavirin beyond 12 weeks. What's the SVR12 result for Arm D of the study? Using the most generous analysis, the SVR12 would be a robust 81% (13/16 patients). But using a stricter calculus, the SVR12 would be a less rosy 65% (13/20 patients). For this reason, pay attention to both the numerator and the denominator used to analyze the upcoming telaprevir data. There are pros and cons for using either calculation, which go a long way toward explaining why there's so much uncertainty about the upcoming presentation. (And I did warn you that this column would get wonky.) Other things to keep in mind about the upcoming data: --Pay attention to the side-effect profile of telaprevir and the reporting of any toxicities or adverse events that might have caused patients to discontinue treatment. --The SVR12 data will be a good measure of telaprevir's efficacy, but it's not enough. For a hepatitis C drug to receive FDA approval, patients must have undetectable virus for 24 weeks, or six months, following the end of treatment. Generally speaking, about 50% of treatment-naive hepatitis C patients are cured (achieve SVR24) on the currently marketed drugs. --If Vertex doesn't succeed with its home-run strategy of treating patients for only three months, the game is far from over. As I said above, the majority of patients in the Prove 1 study are being treated with three months of telaprevir in combination with either 24 or 48 weeks of interferon and ribavirin. FROM NATAP WEBSITE: VX-950 Phase 2b PROVE 1 Study Interim Safety & Antiviral Activity ... The U.S.-based PROVE 1 trial is fully enrolled and ongoing. The PROVE 2 study is underway in Europe and is expected to complete enrollment with ... www.natap.org/2006/HCV/122006_06.htm VX-950 HCV Protease Inhibitor Resistance Profile: combination ... Brief Summary: Tara Keiffer from Vertex presented an oral talk at AASLD on VX-950 drug resistance and how to prevent resistance. She presented an analysis ... www.natap.org/2006/AASLD/AASLD_17.htm - 16k VX-950 Hep C Protease Inhibitor "Final results of a phase 1b Multiple Dose Study of VX-950, a Hepatitis C Virus Protease ... In each cohort 2 placebo & 10 patients receiving VX-950. ... www.natap.org/2005/AASLD/aasld_33.htm - 9k VX-950 HCV Protease Inhibitor Resistance Profile "Wild-Type HCV NS3 Protease Re-emerges during Follow-up After 14 Days of Dosing with VX-950 in Patients with Genotype 1 HCV" ... www.natap.org/2006/EASL/EASL_09.htm - 13k PHARMACOKINETIC BOOSTING OF VX-950 AND SCH 503034, INHIBITORS OF ... Both compounds dosed three times daily (VX-950: 750 mg q8h; SCH 503034: 400-800 ... VX-950 and SCH 503034 metabolism is strongly inhibited by ritonavir in ... www.natap.org/2006/EASL/EASL_13.htm - 11k New Data for Investigational Hepatitis C Drug Telaprevir (VX-950 ... In addition, clinical investigators will report that 24 of 26 patients who received telaprevir (VX-950) in two early-stage clinical trials had undetectable ... www.natap.org/2006/AASLD/AASLD_02.htm - 16k VX-950: HCV PROTEASE INHIBITOR INITIAL RESULTS OF A PHASE 1b ... VX-950 is an orally available HCV protease inhibitor. ... --4 log median reductions in HCV RNA & undetectable HCV RNA achieved with 14 days of VX-950 ... www.natap.org/2005/ddw/ddw_11.htm - 11k Initial Results of a 14-Day Study of the Hepatitis C Virus ... A Phase 2 study which will include evaluation of a 12-week VX-950-based treatment ... In a 14-day study in chronic hepatitis C patients, VX-950 was well ... www.natap.org/2006/EASL/EASL_12.htm - 13k Hepatitis C Selected Articles 28 Days of the Hepatitis C Protease Inhibitor VX-950, in Combination With ... VX-950-New HCV Protease Inhibitor-Shows Potency in 14-Day Study - (05/12/05) ... www.natap.org/hcv.htm