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HCV Standard of Care Controversy: report from FDA Hearing; what can new era of HCV antivirals offer by Ira Jacobson; Key Treatment Outcomes for Boceprevir & Telaprevir, Essentially Doubling SVR Rates
  Reported by Jules Levin
A very important discussion occurred at the very end of the FDA meeting yesterday, that is what is the new "standard of care (SOC)" for HCV. Clearly after the 2 new HCV protease inhibitors are approved, probably within a month, boceprevir or telaprevir in combinatin with peginterferon+ribavirin become the new SOC. Does this make peg/rbv no longer the standard of care, FDA officials asked the committee to comment on. I say YES, it now becomes unethical to use Peg/rbv in new studies. Well, this affects the 2 phase 3 studies started recently by Tibotec for their new HCV protease inhibitor TMC435 and for Boerhinger Ingelheim's new HCV protease inhibitor BI201335, which was announced yesterday that they started enrolling for their phase 3 study. In both studies peg/rbv is the comparator arm treatment. In addition for future planned studies what should the comparator study arm be: peg/ifn or one of the 2 new protease inhibitors plus peg/rbv. I say the latter. In addition this creates a conundrum for HCV/HIV coinfection because we have yet to characterize understand the outcome of treatment for coinfection with the 2 new HCV protease inhibitors in coinfected patients although recently preliminary data in a small group of coinfected patients receiving telaprevir+peg/rbv was presented at a conference yet the boceprevir coinfection study remains ongoing with no data yet reported. The drug-drug interactions between HIV ARTs and the 2 new HCV protease inhibitors are a concern and there are many unanswered questions about these interactions and how to use them together with the 2 new HCV drugs. In the coinfection telaprevir study patients were taking Reyataz/r or efavirenz and in preliminry analysis the early outcomes were pretty similar to that seen in HIV-uninfected but we have yet to see SVR data, the study was small, and there were serious interactions reported with some other key HIV ARTs. The other important issue NOT discussed yesterday is what should be the comparator arm SOC in future studies of new drugs in treatment-experienced patients. So why is this important. If you are for example studying the 2 new Pharmasset nucleotides in treatment-experienced patients, is using one of the new HCV PIs+peg/rbv acceptable considering this may perform less well, patients may not want to enroll in the study since they can get the new drugs through their clinicians and perhaps such a study is now not ethical.
"WHAT CAN a New Era of Antivirals Offer:
In the opening presentation Ira Jacobson, Cornell Medical College in NYC, gave a great talk addressed the burden of HCV we are facing that was well received by the audience. There is a decreased quality of life for HCV+ individuals that might include although symptoms var for individuals: fatigue, weight loss, depression, muscle wasting, impaired cognition. Decompensated cirrhosis & liver cancer (HCC) are increasing, tripling in rates over the past 20 years, and peaking in the next few years, due to the aging HCV patient population. Jacobson presented data showing: HCC has the fastest growing death rate in the US among cancer mortality rates, more than double compared to other leading causes thyroid, esophagus, lung & bronchus, testis, corpus & uteris, and all other cancers. Prevalence of cirrhosis was 9% in 1996 in the VA and 18% in 2006 (p<.001), decompensated cirrhosis 5% in 1996 vs 11% in 2006 (p<.001), and hepatocellular carcinoma (HCC) 0.07% in 1996 & 1.3% in 2006 (p<.001). HCV is not just a liver disease: "other diseases associated with HCV - diabetes, B cell proliferative disorders (essential mixed cryoglobulinemia, non-Hodgkin's lymphoma), depession & cognitive disorders, arthritis ans Sjogren's syndrome. "The biological features of HCV make it potentially curable". "Studies show that SVR is associated with improved outcomes: improved histology (fibrosis of the liver, condition of the liver, stage of liver disease) and the clinical benefit for the patients are decreased decompensation, prevents de novo esophageal varices, decreases risk of hepatocellukat carcinoma, and decreases mortality". "SVR improves outcomes in patients with HCV-associated advanced fibrosis, results from HALT-C Study: reduced rates of decompensated liver disease in patients with SVR vs nonresponders 13% vs 1.3%, reduced liver transplantation to 0.7% from 11%, reduced HCC from 9.1% to 1.4%, reduced liver-related death to 0.7% from 6.8%. "WHAT CAN a New Era of Antivirals Offer: marked increase in SVR (cure), reduction in treatment duration in far more patients than currently possible, prevent many complications, transplants & deaths, and reverse current tide of increasing morbidity & mortality.
Key Treatment Outcomes for Boceprevir & Telaprevir, Essentially Doubling SVR Rates:

Let's review some key highlights of the data, key treatment outcomes reported & reviewed at the FDA hearings for boceprevir & telaprevir over the past 2 days. First the boceprevir data. Now, let me comment that the boceprevir data is more complicated & harder to follow. The Vertex studies were designed to be more simple & therefore are easier to understand the results, while the Merck studies are more nuanced & therefore more complicated & harder to interpret. In phase 3 studies treatment-naive caucasian patients achieved 67% (ITT) - 70%(mITT) SVR rate with either 24 or 48 weeks of triple therapy vs 40% for patients receiving peg/rbv, former standard of care. For Blacks, the SVR rate was 53% for 48 weeks of boceprevir+peg/rbv and 42% with RGT (response guided therapy), which includes patients with a shortened duration of therapy. What is RGT: if after checking viral loads at certain prespecified early time points, in this study weeks 8 & 24, viral load is undetectable a patient is eligible to consider shortened duration of therapy, in this case 28 weeks. Its important to note that 44% of patients received shortened duration of therapy of 28 weeks and there is a 4-week lead-in period where patients receive only peg/rbv and then can add boceprevir. By the way Merck presented data at EASL recently that week 4 responses to the peg/rbv leadin also predicts SVR rates with a 1 log viral load reduction predicting a better SVR rate compared to a viral load reduction of <1 log. Patients who were "Early Responders", undetectable viral load at weeks 8-24, the SVR rates were 96% and could receive either 24 or 48 weeks therapy. For "late-responders" (undetectable at week 24 but detectable at week 8) the Merck analysis was 72% with RGT & 75% with 48 weeks therapy, but with the FDA analysis the SVR rate was 66% for RGT & 75% for 48 weeks, my recollection is the Merck analysis may be better but this does bring to attention the discussion held at the hearing that perhaps late responders should consider a full 48 weeks therapy. This of course brings into discussion the duration of therapy for hard to treat patient populations specifically blacks & cirrhotics who ought to strongly consider a full 48 weeks therapy. Its important to note here that the FDA committee discussed the viability of shortening duration of therapy for specific difficult-to-treat patient populations specifically blacks and cirrhotics.
In treatment-naives the SVR rate in patients with F0/1/2/3 (fibrosis stage of disease) was 72% with 48 weeks therapy & 72% with RGT, for F4 41% in whites and for Blacks with F0/1/2/3 54% with 48 weeks therapy & 50% with RGT and for Blacks with F4. The numbers of patients in all these subgroup populations of Blacks tend to be small so the outcomes are not as sure, but they do suggest that both Blacks & cirrhotics are likely to have better SVR rates, better chance for cure with a full 48 weeks of therapy which the FDA suggested at the hearing should be 32 weeks of boceprevir in a total of 48 weeks of peg/rbv. For treatment-experienced patients, the study included relapsers and partial responders but did not include null responders (I'll address null responders later), the overall SVR rate was 59% in the RGT arm and 66% in the 48 week arm vs 21% for peg/rbv. For cirrhotics 48 weeks therapy had a 77% SVR rate vs 35% for RGT suggesting 48 weeks is much better. For patients with F0/1/2/3 for previous non-responders 8% (2/24) achieved SVR, 47% SVR with RGT (BOC) & 51% with 48 weeks (BOC), while for previous relapsers the SVR rates were 33% with peg/rbv, 74% with RGT & 75% with 48 weeks. For "Early Responders" (defined in this study as undetectable viral load at weeks 8 through 12 and received at least 36 weeks therapy, 44% met the criteria for early response: 89% SVR rate with RGT, 97% with 48 weeks, for non-cirrhotics 91% with RGT & 96% with 48 weeks. These data again raised the question of should harder to treat patient populations including nonresponders, blacks & cirrhotics and of course black cirrhotics & black nonresponders, receive shorter or full durations of therapy. Apparently these patient populations in some cases can achieve SVR with shorter duration of therapy, so if such a patient is undetectable at weeks 8, 12 and 24 can you successfully stop therapy after 36 weeks (36 weeks is the shorter duration of therapy used in the boceprevir study of treatment-experienced patients) in the case of treatment-experienced or 28 weeks for treatment-naives, this was a major discussion at the meeting with varying opinions. The FDA is expected to address this in the product label. I think these are questions that will be interpreted by clinicians & patients and will be the subject of further discussion in the future. It is important to keep in mind that longer duration of therapy does come with increased risk for side effects including anemia but the SVR rates can be higher. Regarding null responders, the phase 3 study did not include them because a phase 2 study suggested they might not respond so well. But Merck did a post hoc analysis looking at patients who had < 1 log viral load reduction at week 4 in this study and extrapolated that these could be considered null responders and found these patients had a approximate 32% SVR rate, but the criticism offered by some observers saying this is hard to interpret because not all 4 week 1 log viral load reduction responders are all the same, that a patient can have a 1 log viral load reduction at week 4 but a 2 log viral load reduction at week 12 so perhaps they were not really a null responder while another patient can have a 1 log viral load reduction at week 4 and no more at week 12, so some on the committee suggested a prospective study looking at null responders.Merck & the FDA presented post-hoc analysis that null responder patients receiving peg/rbv only in the naive & treatment-experienced with (SPRINT2 & RESPOND2) ╩who achieved <2 log reduction during 1st 12 weeks 0 or almost 0 patients achieved SVR. Merck reported patients with <1 log drop at week 4 in SPRINT2/naives, 28% achieved SVR in RGT arm & 38% in BOC/PR48. In RESPOND2/treat-exp 33% achieved with in RGT & 34% in BOC/PR48. The FDA presented that subjects with <0.5 log drop 0% with PR, 28% in RGT and 30% in 48 weeksBOC/PR achieved SVR; patients with <1 log viral log drop at week 4, 4% with PR achieved SVR, 28% with RGT, and 38% with PR4/BOC+PR44 achieved SVR. But this is a post-hoc analysis and I think the ciricism mentioned above still applies and a prospective study should be conducted.╩Boceprevir Side effects: anemia is the main adverse event, this will be managed with ribavirin dose reductions and EPO. The committee concluded anemia can be managed.
The telaprevir data:
Overall SVR for treatment-navies 79% with 12 weeks of telaprevir and either 24 weeks shortened duration of therapy or 48 weeks, along with peg/rbv, 72% with 8 weeks of telaprevir (if you want to shorten duration of telaprevir use as during weeks 8 & 12 there is a risk increased for rash), vs 46% for peg/rbv. 58% of patients were eligible to shorten duration of therapy to 24 weeks if they achieve eRVR (RVR is undetectable at week 4, eRVR is undetectable at week 12 also: although perhaps in this study RVR was defined as <1000 copies viral load at week 4, I think this will be decided by the FDA what this cutoff will be) and there is no 4-week leadin with peg/rbv, patients start with triple therapy. Patients with eRVR "Early Response", 92% SVR rate with 12 weeks telaprevir, 87% with 8 weeks telaprevir, with 24 weeks therapy. Patients withoutout eRVR, so they has RVR but not ERVR, 60% SVR with 12 weeks telaprevir & 52% with 8 weeks telaprevir. FIBROSIS: patients with no, mild or portal fibrosis 82% SVR with 12 weeks telaprevir, 77% with 8 weeks & 49% with peg/rbv alone; patients with bridging fibrosis or cirrhosis: 66% SVR with 12 weeks telaprevir, 53% with 8 weeks, vs 36% with peg/rbv alone. RACE or ETHNICITY: for whites 79% SVR with 12 weeks telaprevir, 73% with 8 weeks vs 48% with peg/rbv; for blacks/African-Americans: 62% with 12 weeks telaprevir, 60% with 8 weeks, vs 29% with peg/rbv; for Latinos: 77% with 12 weeks telaprevir, 68% with 8 weeks, vs 39% with peg/rbv alone. Patients with an eRVR, the ILLUMINATE Study found the same SVR rate with 24 or 48 weeks. Treatment-Experienced, all received 48 weeks therapy: this study looked prospectively at null responders - prior partial responders: 61% SVR; 85% for relapsers; 32% for null responders. Vertex reported brand new information never before presented on 24 weeks therapy pooled from 2 other studies for prior relapsers suggesting that prior relapsers could get 24 weeks therapy: in study 106 67% had eRVR and 89% had SVR and in study 107 96% had eRVR & 100% had SVR. These data are pretty good in suggesting that prior relapsers could use 24 weeks of therapy if they have an eRVR, the FDA will address in the product label. SAFETY: rash and anemia are the 2 adverse events associated with telaprevir. The discontinuation rates are low though due to these side effects and both side effects are manageable. Vertex presented a rash management program including treatment strategies that was well received by the committee, that the adverse events can be managed, Vertex also said they plan to educate patients & clinicians about managing the rash & anemia.
My report From Yesterday Immediately After the FDA Committee Vote
The panel in discussion mostly agreed that Response Guided Therapy could be used for prior relapsers and certainly RGT is compelling for treatment-naives which means if viral load is undetectable at weeks 4 and 12 then 24 weeks therapy is good enough. A couple of panelists expressed concern about RGT for relapsers suggesting more data is needed, perhaps RGT for prior relapsers should be on a per patient basis. For blacks and cirrhotics the data certainly supports a recommendation for telaprevir use, the data was very good for blacks. The panel discussed what additional studies we would like. What role will IL28b play in RGT for blacks and cirrhotics? We need more data to inform on RGT in these patient populations.
Resistance: retreatment should be studied, panelist commented, and we need to be careful about resistance. We should study adherence and the affect of education. Followup on RGT in relapsers. More studies in blacks needed. Further study of twice daily vs three times daily dosing. Looking at anal rectal side effects.
The panel recommends that boceprevir and telaprevir should be the new comparator or control arm in efficacy studies in the future for new drugs, the new standard of care, instead of pegintereron+ribavirin. And of course I agree with this and that studies should be non-inferiority studies. We need a regimen without peg/rbv, one panelist said this is important.
One point I would like to raise, if we have a regimen with 2 nucleoties or with a NS5A plus a nucleotide how would you study this in treatment-experienced patients in the sense that a tripe regimen of a protease plus peg/rbv may not be an effective regimen for treat+exp patients. One panelist said what about ongoing phase 3 studies now using peg/rbv as a control arm after these 2 new drugs are approved.
Vertex received quite a bit of praise for their development program by the FDA panel.
Tha panel was very excited about the major leap forward telaprevir brings to HCV treatment, that we can cure 80% of treatment-naive patients with telaprevir.
There is risk for getting a skin rash with use of telaprevir but the panel roundly agreed it is well manageable.
One panelist said it would be unusual to have an effective therapy for a life threatening disease, referring to HCV, without a serious adverse event Education for clinicians and patients about potential rash received a lot of discussion. The FDA panel congratulated Vertex on doing a good jopb on preparing an education program for clinicians and patients on the rash and also the panelists said Vertex conducted good studies in general and in having conducted a HIV coinfection study.
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