2010 AASLD Liver Meeting

New HCV Drugs at AASLD, easy to understand report: (see links below to reports from AASLD)

By Jules Levin

The major news is that boceprevir and telaprevir, the 2 new oral HCV protease inhibitors reported their phase 3 data, it looked good with 75% for telaprevir & 67% for non-black patients with boceprevir (both taken with peg/rbv) achieving a cure; studies examined genotype 1 patients only. For blacks 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.

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: 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,.

Boerhinger Ingelheim also 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.

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.

Phase 3 data was reported for the new HCV protease inhibitors telaprevir from Vertex and boceprevir from Merck (Schering). Patients will take telaprevir for 12 weeks + peg/rbv, stop telaprevir after 12 weeks but continue taking peg/rbv for another 12 weeks. For telaprevir (plus peg/rbv) 75% of patients achieved SVR or cures. 68% of patients in studies had undetectable HCV viral load at 4 weeks and 58% at weeks 4 and 12, 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. Relapse rates were low, 9%. On-treatment virologic failure rates were only 3%. Patients with no, mild or portal fibrosis did a little better with a 78% cure or SVR rate. Patients with cirrhosis or bridging fibrosis had a less response with a 62% cure rate. For African-Americans the cure rate was 62% and for Latinos 74%.

In a separate press announcement Vertex reported that Blacks with undetectable HCV viral load at weeks 4 and 12, 88% achieved a cure, very good news. 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. Previously Vertex reported prior treatment-experienced patients 65% achieved SVR: 86% for relapsers, 57% for partial responders, 31% for null responders.

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. 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 week 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. 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 telaprevirpeg/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 nethese 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.

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)

<http://natap.org/2010/AASLD/AASLD_22.htm> – (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 <http://natap.org/2010/AASLD/AASLD_23.htm> – (11/03/10)

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AASLD: 5 New Potent HCV Protease inhibitors <http://natap.org/2010/AASLD/AASLD_41.htm> – (11/05/10)

AASLD: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist <http://natap.org/2010/AASLD/AASLD_40.htm> – (11/05/10)

AASLD: HCV Late Breaker Posters this Morning at AASLD…..ABT450, BMS790052 NS5A+proteaseBMS650032, BI 201335+HCV polymerase inhibitor BI 207127+ribavirin http://natap.org/2010/AASLD/AASLD_09.htm  – (11/02/10)
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ALL 60 REPORTs ARE HERE:61th Annual Meeting of the American <http://natap.org/2010/AASLD/AASLD.htm>
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 < http://natap.org/2010/AASLD/AASLD_54.htm > – (11/08/10)

Vertex’s telaprevir and Merck’s boceprevir: Compliance and resistance issues due … <http://www.natap.org/2010/AASLD/AASLD_03.htm>
Nov 3, 2010 … Both companies will present final Phase III study results at the upcoming American Association for the Study of Liver Diseases (AASLD) … http://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 < http://natap.org/2010/AASLD/AASLD_17.htm > – (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’ < http://natap.org/2010/AASLD/AASLD_04.htm > – (11/01/10)

AASLD: Bristol-Myers, Gilead and other companies Seek AIDS Cocktail Success in Hepatitis C: ’2 oral HCV drugs in combination’ < http://natap.org/2010/AASLD/AASLD_02.htm > – (11/01/10)

AASLD: Black patients (& new HCV therapy) fare well on Vertex hepatitis C drug < http://natap.org/2010/AASLD/AASLD_01.htm > – (11/01/10)

AASLD: Sustained Virological Response of Antiviral Therapy and Clinical Outcomes in Elderly Patients with Compensated HCV – related Cirrhosis < http://natap.org/2010/AASLD/AASLD_31.htm > – (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) . < http://natap.org/2010/AASLD/AASLD_26.htm > – (11/04/10)

AASLD: Clinical, Virological, Biochemical Outcomes After 20 Years of Sustained Virological Response (SVR) in Chronic Hepatitis C: The NIH Experience. < http://natap.org/2010/AASLD/AASLD_25.htm > – (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 < http://natap.org/2010/AASLD/AASLD_33.htm > – (11/04/10)