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New HCV Drugs at AASLD, easy to understand report:
(see links below to reports from AASLD)
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By Jules Levin
from jules: So what happened at AASLD, briefly. The major info is that boceprevir and telaprevir, the 2 new oral HCV protease inhibitors reported their phase 3 data, it looked good with overall 75% for telaprevir (62% for Black/African-American) & 67% for non-black patients with boceprevir (both taken with peg/rbv), studies examined genotype 1 patients only. Some patients were able to achieve SVR with 24 weeks therapy while some had 36 or 48 weeks therapy (see discussion below). For results in African-Americans/Blacks see discussion below. For Blacks/African-Americans response rates were very high with both drugs as with whites for patients who achieved very early viral responses, undetectable by weeks 4 and 12 for telaprevir and week 8 and 24 for boceprevir (see data below). It's expected the FDA will hold a public hearing & approve both drugs during the Summer of 2011. An interesting study at AASLD found that after 2 yrs HCV telaprevir resistance mutations that emerged in patients who did not achieve SVR, that in 89% of these patients the mutations were no longer detectable after 2 years on average with sensitive lab testing, with clonal sequencing. This helps to enrich our discussion about resistance, see link immediately below.
AASLD: Telaprevir Resistance Disappears in 89% of Patients: Long-Term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis from the EXTEND Study - (11/03/1)
What else happened? These studies also were conducted only in genotype 1 patients. Probably the most anticipated story was the results from the BMS study looking at 2 oral drugs, their protease+ their NS5A inhibitor alone with peg/rbv in null responders. The response rate was about 50% after 12 weeks therapy but interestingly genotype 1a were the failures, genotype 1bs did not fail. Of note 9/10 patients, receiving peg/rbv plus the 2 orals had undetectable viral load after 12 weeks! Also of note patients who failed after taking only the 2 orals, most achieved undetectable by continuing with peg/rbv only, also very interesting. This information increases our knowledge about whether we can get rid of peg/rbv at least for some patients, but so far we don't have an answer, final results from this study will provide more information and they should be available in 2011. Other HCV protease inhibitors are in earlier development and some look more potent, although they are still in earlier stages of development: Abbott's ABT-450, Tibotec's TMC435, Merck's 5172 and 7009; also Boerhinger Ingelheim has a protease moving along. BMSs NS5A inhibitor is potent, and Presido reported on their NS5A inhibitors in early pre-clinical development but going into patients study soon. The NS5A drugs look potent & the BMS drug is the furthest along. R7128 is a nuke, a polymerase inhibitor, and Roche reported very interesting & good results showing after 12 weeks of R7128+peg/rbv 88% of patients had undetectable viral load. As well, Pharmasset is developing 2 nucleotides 7977 & 938, which look very potent, both showing as much as 4.5 log reductions. These classes of drugs are important because they do not appear to show drug resistance develops easy as we see with protease inhibitors, so they provide a lot of interesting promise. Another very interesting development at AASLD was that Gilead has taken a very ambitious jump into HCV announcing they have 7 drugs in development and reporting results of an interesting study with 3 drugs, their protease+their polymerase inhibitor+ribavirin, As well, Boerhinger Ingelheim reported results of 2 orals, their Protease+their polymerase alone and in combination with ribavirin with 17/17 achieving undetectable with all 3 oral drugs.
Of note BMS is developing peg lambda interferon, in case we can't get rid of interferon, the drug appears to be more tolerable, less side effects. The issue of drug resistance remains an open question. The question is: will drug resistance prevent a patient from reusing a protease inhibitor again as it does in HIV unless you have a 2nd generation protease that suppresses resistant virus, we don't know the answer to this question yet. Both drugs boceprevir & telaprevir had posters at the meeting showing drug resistance mutations can emerge (poster reports are on NATAP website), but we still don't know if they will persist and emerge again later if a protease is reused. Of particular note, Merck is developing a protease MK-5172, which shows it might suppress resistant virus but also looked very potent in the study reported at AASLD, so it might also be a firstline therapy because it looks so potent. Compliance (adherence) and the risk of developing drug resistance will be big concerns. Response Guided Therapy is important, this is as discussed below how we will be able to see if patients are responding well early on after weeks 4, 8 and 12, so if patients are not responding well they can stop the drugs and hope to prevent drug resistance. There will have to be major support programs devoted to the implementation of this & education for clinicians and patients.
It is crucial to success with a new therapy regimen that includes an orally taken HCV protease inhibitor plus Peg/rbv to take every dose as instructed (this is called good adherence or compliance), one must follow directions on how to take each drug as told. This is because drug resistance to the oral HCV protease inhibitors can develop quickly if one misses a dose, doesn't take the entire dose, takes a dose late, or if one doesn't follow instructions regarding food intake when taking each dose. Once drug resistance develops this can lead to the regimen failing. In addition one should also closely follow instructions for taking the peginterferon and the ribavrin. Following instructions exactly as told will give one the best chance to succeeding with therapy and achieving a cure of HCV. As well after starting therapy one's clinician or doctor will tell the patient to return after a certain amount of time to check HCV viral load, this is also crucial so as to monitor if therapy is successful in reducing viral load, because if viral load levels do not decline enough to meet certain thresholds a patient may be requested to stop this therapy, this is important to prevent drug resistance from developing to the oral HCV protease inhibitor.
Genotype 1a vs 1b appears to matter: 1a appears to respond less well to protease inhibitors than genotype 1b because drug resistance appears more likely to emerge with 1a so therapeutic approaches that will likely be more effective for 1a include more potency, boosted PIs are likely to be more effective and nucleosides like R7128 and nucleotides like PSI7977 and PSI938 as well because it appears they don't develop resistance easily. HOWEVER, Vertex will present in the near future the response rates to telaprevir for both patients who are 1a or 1b genotype, and we will then see if it matters. As well, Merck will present the same results regarding boceprevir.
Telaprevir
Phase 3 data was reported for the new HCV protease inhibitors telaprevir from Vertex and boceprevir from Merck (Schering). For telaprevir (plus peg/rbv) 75% of patients achieved SVR or cures. Some patients received a total of 24 weeks therapy, other patients received a total of 48 weeks therapy. Telaprevir is taken only for 12 weeks, peg/RBV is taken during the entire 24 or 48 weeks. In study slides at AASLD it said "eRVR (extended RVR, which is week 12 timepoint) = HCV RNA undetectable at week 4 and week 12"; telaprevir (TVR) Stopping Rules said: week 4 criteria for stopping HCV RNA >1000, week 12 criteria for stopping HCV RNA <2 log decline.
68% of patients in studies had undetectable HCV viral load at 4 weeks and 58% at weeks 4 and 12 (212/363), and 89% of these patients with undetectable viral load at weeks 4 and 12 achieved a cure or SVR after 24 weeks of total therapy, for these patients 24 weeks therapy achieved SVR. But for patients who did not achieve eRVR, that is who did not meet the required viral load at week 12 (undetectable presumably), the other 42% (151/363), they received a total of 48 weeks therapy, and the SVR rate for this group was 54% compared to the 89% who had an eRVR at week 12 and therefore qualified to take only 24 weeks therapy. When you combine both these groups you get an overall 75% SVR rate.
Relapse rates were low, 9%. On-treatment virologic failure rates were only 3%. Patients with no, mild or portal fibrosis had a 78% cure or SVR rate. Patients with cirrhosis or bridging fibrosis had a less response with a 62% cure rate, and for African-Americans the cure rate was 62% and for Latinos 74%. Although these results were not broken down by duration of therapy in the slide presentation (24 or 48 weeks), in the ILLUMINATE Study reported at AASLD, Black/African-Americans with eRVR (undetectable HCV viral load at weeks 4 and 12), 88% achieved a SVR with 24 weeks therapy. Vertex reported 56% of patients experienced a 'rash event', 6% a severe rash event, 7% discontinued telaprevir due to rash event, only 1.4% discontinued all study drugs (peg/rbv) due to rash events. 4% of patients discontinued telaprevir for anemia, on average hemoglobin went down from 12.3 g/dL approx to 11 by week 8.
What about telaprevir studies in prior treatment-experienced patients?
65% of People Whose Prior Treatment for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase 3 REALIZE Study (31% null responders) - (09/07/10)
Sept 7 Vertex issued a press release reporting results from the REALIZE Study: : The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one prior treatment with interferon-based therapy. There were two telaprevir-based arms (simultaneous and delayed start: PR lead-in) and one control arm. In REALIZE, the telaprevir arms included 12 weeks of telaprevir in combination with pegylated-interferon and ribavirin with 36 weeks of pegylated-interferon and ribavirin alone for a total of 48 weeks of treatment. 86% of relapsers (245/286) achieved SVR, 57% of partial responders (55/97), 31% of null responders (46/147), overall 65%.
Telaprevir in Null-Responders & Non-Responders
Vienna, Austria, Telaprevir in Null-Responders & Non-Responders. Reported by Jules Levin EASL Apr 14-18 2010. Vienna Austria.
www.natap.org/2010/EASL/EASL_03.htm
In this telaprevir treatment-experienced study presented at EASL April 2010, 55% of prior partial responders achieved SVR with 24 weeks therapy (n=29), 97% of relapsers (n=29), and 75% of prior viral rebounders (n=8). There were 51 null responders in the study, 41% achieved RVR (undetectable at week 4): 21% (5/24) in the T12/PR24 group, 59% (16/27) in the T12/PR48 group; 37% achieved SVR (19/51): 17% (4/24) in the T12/PR24 group, 55% (15/27) in the T12/PR48 group.
Boceprevir
For boceprevir (plus peg/rbv) in the phase 3 data reported at AASLD in SPRINT2 Study in genotype 1 treatment-naïve patients, 67% to 71% of non-black patients achieved SVR and 42% to 53% of Blacks achieved SVR; the 42% refers to patients who received either 24 or 48 weeks therapy, and the 53% refers to patients who received 48 weeks therapy. In this study patients received a 4-week lead in with peg/rbv before starting boceprevir, so the drug will likely be used this way in the clinic. Patients with a 1 log or more decline in viral load after the 4-week lead-in, 82% achieved SVR. Patients with undetectable viral load at week 8, 90% achieved SVR. Patients who were undetectable at weeks 8 through 24, 97% achieved SVR. But if viral load was detectable once during that time, often week 8 (late responders) but undetectable at week 24, 74% achieved SVR with >28 weeks therapy (36, 48 weeks); 47% of non-blacks received 28 weeks therapy, 22% received >28 weeks (36, 48 weeks). So, if a patient was undetectable at weeks 8 and 24, 97% achieved SVR whether they went for 28 or 48 weeks, so shorter duration of therapy is ok for these patients, that's key information. But for these non-black patients if they were detectable at week 8 but undetectable at week 24, late responders they should go for 48 weeks. For Blacks, the numbers of patients in each subgroup are small (about 155 blacks in entire study): for patients undetectable at weeks 8 and 24, 87% achieved SVR (13/15) with 28 weeks therapy and 95% (18/19) with 48 weeks; if they were detectable one time between weeks 8-24 58% (7/12) and 88% (7/8) achieved SVR after 48 weeks. Essentially Blacks are not as responsive but we knew that, so although in general longer duration of therapy was more effective for Blacks, the SVR rate was high also for Blacks as well as Caucasians if they had undetectable viral load at weeks 8 and 24. Boceprevir will be given for 24 weeks.
49% of patients experienced anemia, 1% discontinued due to anemia, 13% had dose reductions due to anemia, 24% used EPO for treatment of anemia. Anemia also occurred for patients taking telaprevir+peg/rbv but at a lower rate.
Merck also presented results from RESPOND2, which only examined patients who were previous peg/rbv non-responders (decrease of HCV viral load of 2 logs or more by week 12 of prior therapy but with detectable viral load after that and relapsers). 59%-66% achieved SVR. If patients were undetectable by week 8 87% achieved SVR, 46% of the study patients were eligible to stop after 36 weeks therapy so SVR rate was the same whether you went 36 or 48 weeks. They don't distinguish between whether these were nonresponders or relapsers but you have to assume many or the majority of these SVR responders were relapsers. Week 4 lead-in response predicted SVR: if a patient had 1 log or more decline in viral load at week 4 73-79% achieved SVR. 26% of patients had <1 log reduction in viral load. The data presentations on boceprevir were not very clear/well explained, a little confusing.
Tips For Successful HCV Therapy: manage side effects, good adherence
from Jules: There are a few key important pointers to stress that may be repetitive, for those of you who don't already know this: mutations associated with drug resistance to HCV protease inhibitors pre-exist in the HCV in patients. If a patient were to take only the HCV protease inhibitor without taking additional drugs, in this case peg/rbv but in the future additional oral HCV drugs from other classes, viral load would go down initially but HCV protease inhibitor drug resistance mutations can emerge within days and cause viral load to increase/rebound and failure of the drug. But taking peg/rbv and other HCV drugs along with the protease inhibitor and complete adherence suppresses virus replication and prevents the mutations from emerging. There is one EXCEPTION: for patients who are previous 'null-responders', these are patients who previously have taken peg/rbv therapy and had very little response to it, it is defined as achieving <2 log reduction in viral load within the initial 12 weeks after having started peg/rbv when they were previously treated. A patient may not have ever taken peg/rbv previously but may be a null-responder if that patient took it now. Having a reasonably good response to peg/rbv is important when taking boceprevir or telaprevir along with peg/rbv. It is important to know if a patient was a previous null-responder because you can expect a similar response to peg/rbv when taking it again this time along with boceprevir or telaprevir, which means peg/rbv will not be as effective in suppressing viral load and the potential for pre-existing mutations to emerge, but the new triple drug therapy regimen can still achieve SVR for these patients as well. Taking 2 or 3 oral HCV drugs plus peg/rbv would be more effective in preventing drug resistance from emerging and achieving an SVR, but at this time only boceprevir and telaprevir are ready for FDA approval, additional oral HCV drugs are in earlier development and won't be ready for the pharmacy for several more years. There are a few additional things to keep in mind to succeed with the new therapy that is expected to be available around the Summer of 2011, boceprevir or telaprevir + peg/rbv. Each drug is associated with unique side effects: peg/rbv with fatigue (anemia), depression; telaprevir with skin rash, boceprevir with additional anemia (see discussion of this below. These side effects do not occur for everyone taking the drug but for a percentage of patients. It is crucial to manage these side effects so they don't lead to discontinuing therapy. In some cases anti-depressants can be used by starting them either before or after initiating therapy. EPO can be used to manage anemia and associated fatigue. Vertex will announce a management strategy for skin rash if it emerges. It is important to be aware of these issues and for a discussion to take place about them between patient and clinician, and for both to be properly prepared to begin therapy. One last point. For both HCV protease inhibitors 'Response-Guided Therapy' will be utilized, which means at certain set times viral load will be tested by taking blood early on after starting therapy, so if a patient does not achieve a certain pre-determined reduction in viral load at each time point they will be instructed to stop therapy, this is done to hopefully prevent drug resistance from developing. The time points will be pre-described for telaprevir and will likely be at week 4 and 12 after therapy begins, because these were the time points use in the studies described below. For boceprevir, they used week 8 and week 24 in their studies, but that does not mean it might not still be useful to test viral load at additional time points.
here are the slides for these studies presented at AASLD:
AASLD: Phase 3 - Response Guided Therapy (RGT) - Boceprevir Combined with peginterferon alfa-2b plus ribavirin for treatment-naïve patients with HCV genotype 1 (SPRINT-2 Final Results) - (11/03/1)
AASLD: Telaprevir in Combination with Peginterferon alfa-2a and Ribavirin in Genotype 1 HCV Treatment-Naïve patients: Final results of Phase 3 ADVANCE Study - (11/03/10)
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AASLD: 5 New Potent HCV Protease inhibitors - (11/05/10)
AASLD: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist - (11/05/10)
AASLD: HCV Late Breaker Posters this Morning at AASLD.....ABT450, BMS790052 NS5A+proteaseBMS650032, BI 201335+HCV polymerase inhibitor BI 207127+ribavirin - (11/02/10)
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ALL 60 REPORTs ARE HERE:
61th Annual Meeting of the American
Association for the Study of Liver Diseases
Boston, MA, Hynes Convention Center
October 30-November 3, 2010
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AASLD: HCV New Drugs - (11/08/10)
Vertex's telaprevir and Merck's boceprevir: Compliance and resistance issues due ...
Nov 3, 2010 ... Both companies will present final Phase III study results at the upcoming American Association for the Study of Liver Diseases (AASLD) ...
www.natap.org/2010/AASLD/AASLD_03.htm
**** AASLD: Merck's Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure And Treatment-Naïve Adult Patients With Chronic Hepatitis C Genotype 1 Compared To Control - merck press release - (11/03/10)
**** AASLD: Telaprevir+pEg/RBV Based Combination Therapy in People with Hepatitis C, Regardless of Race or Stage of Liver Disease - 'up to 88% in African-Americans' - (11/01/10)
AASLD: Bristol-Myers, Gilead and other companies Seek AIDS Cocktail Success in Hepatitis C: '2 oral HCV drugs in combination' - (11/01/10)
AASLD: Black patients (& new HCV therapy) fare well on Vertex hepatitis C drug - (11/01/10)
AASLD: Sustained Virological Response of Antiviral Therapy and Clinical Outcomes in Elderly Patients with Compensated HCV - related Cirrhosis - (11/04/10)
AASLD: Coffee is associated with virologic response in chronic Hepatitis C: Findings from the Hepatitis C Long - Term Treatment against Cirrhosis Trial (HALT - C) . - (11/04/10)
AASLD: Clinical, Virological, Biochemical Outcomes After 20 Years of Sustained Virological Response (SVR) in Chronic Hepatitis C: The NIH Experience. - (11/04/10)
AASLD: Maintenance peginterferon (pegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis C: extended follow - up results from the HALT - C Trial - (11/04/10)
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