| |
HCV Protease Inhibitor Resistance - New Monogram Resistance Assay: this report contains relevant information related to HCV telaprevir & boceprevir resistance and the new assay
|
| |
| |
(sources: telaprevir/boceprevir Packages Insert/FDA Briefing document)
At the bottom of this email is the LabCorp press release about the assay and attached are 2 Momogram announcements about the test.
(in phase 3 studies) "Of the 66 boceprevir-treated patients with RAVs detected at baseline, 43 (4%) had V36M, R155K, T54A/S, and/or V55A (RAVs frequently detected in non-SVR patients postbaseline, see Section 9.2) and 23 had V36I/L, Q41H, V55I, V170M and/or M175L (RAVs not frequently detected in non-SVR patients postbaseline). Of the 43 patients who had V36M, R155K, T54A/S, and/or V55A, 36 were interferon responsive and 7 were poorly interferon responsive (as defined at TW 4, see Section 7.2.4). The SVR rate among interferon responsive patients with V36M, R155K, T54A/S, and/or V55A RAVs at baseline (78%; 28/36) was similar to the SVR rate among interferon responsive patients with V36I/L, Q41H, V55I, V170M and/or M175L at baseline (73%; 11/15). In contrast, the SVR rate among poorly interferon responsive patients with V36M, R155K, T54A/S, and/or V55A RAVs at baseline was 0% (0/7), compared to SVR rates of 50% (3/6) among poorly interferon responsive patients with baseline RAVs V36I/L, Q41H, V55I, V170M and/or M175L. Although the numbers of patients are small, the combination of poor interferon responsiveness and V36M, R155K, T54A/S, and/or V55A RAVs at baseline appears to correspond with a poor treatment outcome. The numbers of patients with a combination of poor interferon responsiveness and baseline V36M, R155K, T54A/S, and/or V55A RAVs represented 1% (7/1020) of patients treated with boceprevir."
"Telaprevir-associated resistance substitutions (substitutions at positions V36, T54, R155, A156 or D168) were present at baseline in 5% (117/2239) of the subjects in the combined Phase 3 Studies. Given the small number of subjects with baseline telaprevir resistance substitutions, it is hard to make conclusions on response outcomes when these specific substitutions are present at baseline"
------------------------------------------------
Telaprevir Resistance Disappears in 89% of Patients: Long-Term ...
www.natap.org/2010/AASLD/AASLD_66.htm
Nov 3, 2010 - Telaprevir Resistance Disappears in 89% of Patients: Long-Term Follow-up of ... "these patients are still likely enriched for PI resistant variants
Evolution of Treatment-Emergent Variants in Telaprevir Phase 3 ...
www.natap.org/2011/EASL/EASL_34.htm
Apr 3, 2011 - EASL 2011 Berlin Germany March 30-April 3. JC Sullivan, S De Meyer, DJ Bartels, I Dierynck, E Zhang, J Spanks, A Tigges, N Adda,
--------------------------------------------
BOCEPREVIR RESISTANCE-ASSOCIATED VARIANTS (RAVS ...
www.natap.org/2011/EASL/EASL_35.htm -
Apr 3, 2011 - BOCEPREVIR RESISTANCE-ASSOCIATED VARIANTS (RAVS) ARE OBSERVED MORE FREQUENTLY IN HCV (GT1)-INFECTED PATIENTS
Long-term Follow-up of Patients Treated with Boceprevir in ...
www.natap.org/2010/ResisWksp/ResisWksp_25.htm
International HIV and Hepatitis Drug Resistance Workshop June 8-12, 2010, ... (P/R): Durability of Responses and Rates of Reversion of Resistance Mutations
----------------------------------------
Boceprevir
9.5 Resistance Conclusions
· Boceprevir resistance-associated variants (RAVs) were detected in a small proportion of patients prior to treatment.
· Among all patients treated with boceprevir, as a result of the high SVR rates, the emergence of RAVs was infrequent. However, RAVs were detected in the majority of patients with virologic breakthrough and incomplete virologic response.
· Interferon responsiveness plays a role in the emergence of RAVs on boceprevir treatment.
· After stopping therapy in patients who did not achieve SVR and whose viruses developed RAVs, the number of RAVs declined over time. Different RAVs declined at different rates likely reflecting differing effects on viral fitness.
9.1 Detection of Resistance-Associated Variants at Baseline
Baseline sequence data were available for 980 of 1020 (96%) patients treated with boceprevir in the pivotal Phase 3 studies. Of these, 66/980 (7%) patients had viruses with RAVs detected at baseline. In patients with genotype 1a virus with RAVs detected, the most common baseline RAVs were V36L, V55A, V55I and T54S. In patients with genotype 1b virus with RAVs detected, the most common baseline RAVs was T54S.
Similar results were observed in patients in the PR48 control arms of the pivotal Phase 3 studies. Among patients with baseline sequence data, 27/419 (6%) patients had viruses with RAVs detected at baseline. In patients with genotype 1a virus, the most common baseline RAV detected was V55A. In subjects with genotype 1b virus, the most common baseline RAVs detected were T54S and V170M.
9.2 Detection of Resistance-Associated Variants Postbaseline
The emergence of RAVs was evaluated in a pooled analysis of patients treated with boceprevir in SPRINT-2 and RESPOND-2. The most frequently detected post-baseline RAVs in viruses from these patients were amino acid substitutions V36M or R155K in genotype 1a viruses or T54A, T54S, A156S or V170A in genotype 1b viruses.
Among boceprevir-treated non-SVR patients with samples sequenced; the emergence of postbaseline RAVs was detected in 155/295 (53%). Most non-SVR patients with viruses harboring postbaseline RAVs were poorly interferon responsive (74%; 115/155). The detection of postbaseline RAVs was highly associated with viral breakthrough (detectable HCV RNA after being undetectable) or incomplete virologic response (initial decrease in HCV RNA followed by ≥ 1 log10 increase from nadir); viruses isolated from 75% (18/24) of viral breakthrough patients and 92% (54/59) of incomplete virologic response patients displayed viruses with RAVs. RAVs were detected in viruses isolated from 41% (32/78) of relapsers.
RAVs were detected with similar frequencies in RGT and BOC/PR treatment arms. In the RGT arms, viruses isolated from 52% (82/158) of patients with postbaseline samples sequenced had viruses with detectable RAVs compared to 52% (74/142) of viruses isolated from patients in the 48-week BOC/PR arms.
9.3 Resistance-Associated Variants at Baseline and SVR
An exploratory analysis comparing the frequency and distribution of RAVs detected in boceprevir-treated patients at baseline with the frequency and distribution of post-baseline RAVs detected in non-SVR boceprevir-treated patients indicated that some RAVs at baseline (V36M, R155K, T54A/S and/or V55A) may be associated with treatment failure in poorly interferon responsive patients.
Of the 66 boceprevir-treated patients with RAVs detected at baseline, 43 (4%) had V36M, R155K, T54A/S, and/or V55A (RAVs frequently detected in non-SVR patients postbaseline, see Section 9.2) and 23 had V36I/L, Q41H, V55I, V170M and/or M175L (RAVs not frequently detected in non-SVR patients postbaseline). Of the 43 patients who had V36M, R155K, T54A/S, and/or V55A, 36 were interferon responsive and 7 were poorly interferon responsive (as defined at TW 4, see Section 7.2.4). The SVR rate among interferon responsive patients with V36M, R155K, T54A/S, and/or V55A RAVs at baseline (78%; 28/36) was similar to the SVR rate among interferon responsive patients with V36I/L, Q41H, V55I, V170M and/or M175L at baseline (73%; 11/15). In contrast, the SVR rate among poorly interferon responsive patients with V36M, R155K, T54A/S, and/or V55A RAVs at baseline was 0% (0/7), compared to SVR rates of 50% (3/6) among poorly interferon responsive patients with baseline RAVs V36I/L, Q41H, V55I, V170M and/or M175L. Although the numbers of patients are small, the combination of poor interferon responsiveness and V36M, R155K, T54A/S, and/or V55A RAVs at baseline appears to correspond with a poor treatment outcome. The numbers of patients with a combination of poor interferon responsiveness and baseline V36M, R155K, T54A/S, and/or V55A RAVs represented 1% (7/1020) of patients treated with boceprevir.
9.4 Decline in Postbaseline Resistance Associated Variants in Long-Term Follow-up
Patients enrolled in the long-term follow-up study (P05063) and who had viruses with postbaseline RAVs detectable at the end of their participation in a boceprevir Phase 1, 2 or 3 clinical study had plasma samples monitored every 3 to 6 months to assess for RAVs by population sequencing. A total of 183 patients had sufficient follow-up data to be included in a 2-year interim analysis of the data. (Note: All of these patients had been enrolled in a Phase 2 clinical study.)
The rate of loss of detection of RAVs by population sequencing was calculated in the Kaplan-Meier analysis for the four most common RAVs and for all RAVs (including the most common RAVs) and is shown for patients infected with genotype 1a or 1b virus in Table 24. (Note: These results are from long term follow-up of patients enrolled in Phase 2; the analysis for patients enrolled in the pivotal Phase 3 studies is ongoing.) The loss of detection of RAVs by population sequencing varies depending on the RAV and likely reflects the relative fitness of the specific RAVs.
-------------------------------------
Telaprevir
Telaprevir Treatment-Emergent Substitutions
In a pooled analysis of subjects who did not achieve SVR from the Phase 3 studies, NS3 amino acid substitutions V36M, A or L, T54A or S, R155K or T, A156S, T or V and D168N were determined to emerge frequently on telaprevir treatment. In replicon-based and enzymatic phenotypic assays using site-directed mutants, the V36M/A, T54A or S, R155K or T, A156S amino acid substitutions have been shown to confer 4- to 20-fold reduced susceptibility to telaprevir and substitutions V36M+R155K, A156T, or A156V have been shown to confer >60-fold reduced susceptibility to telaprevir. Variants at position D168, known to confer decreased susceptibility to the macrocyclic NS3/4A protease inhibitors, had not been previously reported to be associated with telaprevir resistance.
Telaprevir-associated resistance substitutions (substitutions at positions V36, T54, R155, A156 or D168) were present at baseline in 5% (117/2239) of the subjects in the combined Phase 3 Studies. Given the small number of subjects with baseline telaprevir resistance substitutions, it is hard to make conclusions on response outcomes when these specific substitutions are present at baseline. However, the limited data indicate that the presence of telaprevir resistance-associated substitutions at baseline do not preclude achieving SVR on treatment with a T/PR regimen.
Study 108: Treatment-Naïve
Overall, the proportion of telaprevir resistance substitutions that emerged on treatment was comparable between the T8/PR and T12/PR arms with more substitutions emerging in subtype 1a than 1b treatment failures. Almost all of the treatment failures who failed on T/PR at Week 12 or earlier had treatment-emergent substitutions and 60% of isolates from subjects who failed after Week 12 on PR or who relapsed had treatment-emergent substitutions. The substitutions V36M and R155K and combination of both emerged most frequently in subtype 1a failures and V36A, T54A or S and A156T emerged most frequently in subtype 1b failures.
Study 111: Treatment-Naïve
In Study 111, a high percentage of telaprevir treatment failures had treatment-emergent substitutions. Of the treatment failures who failed after Week 12 on PR or relapsed on T12-containing regimens, 90% (46/51) had treatment-emergent substitutions. As in Study 108, V36M and R155K and the combination of both emerged most frequently in 50-60% of Subtype 1a failures. In the subtype 1b failures, T54A emerged most frequently.
Study C216: Treatment-Experienced
relapsed. The proportion of treatment-emergent substitutions was also similar between the two arms. Over half the treatment-failure subjects in Study 216 were prior null responders. Consistent with these data, the prior null responders also had the most treatment-emergent substitutions. The V36M and R155K substitutions and the combination of both emerged most frequently in subtype 1a treatment failures. The V36A, T54S or A and A156T, S or V emerged most frequently in subtype 1b failures.
Overall, the number of subjects who did not achieve SVR was similar in the T12/PR48 (36%) and lead-in arm T12(DS)/PR48 (34%). Overall, 70% of subject failing to achieve SVR had treatment-emergent substitutions when they experienced failure on treatment or relapsed. The proportion of treatment-emergent substitutions was also similar between the two arms. Over half the treatment-failure subjects in Study 216 were prior null responders. Consistent with these data, the prior null responders also had the most treatment-emergent substitutions. The V36M and R155K substitutions and the combination of both emerged most frequently in subtype 1a treatment failures. The V36A, T54S or A and A156T, S or V emerged most frequently in subtype 1b failures.
Persistence of Telaprevir Resistant Variants/Follow-up Analysis
Study 112 is an on-going, 3-year, virology follow-up study in subjects previously treated with telaprevir from Phase 2 clinical trials. In this study, changes in telaprevir resistance-associated HCV variants over time are evaluated in subjects who did not achieve an SVR24 and had developed one or more telaprevir resistance-associated substitutions. In this interim analysis, follow-up periods in Study 112 range from 5 - 40 months with a median of 25 months. A total of 56 subjects were used for the analysis of persistence of resistant variants V36A/M/L, T54S/A, R155T/K/I, and A156S/T in the absence of telaprevir selection. Figure 4 shows the percentage of variants (V36M, T54A and S, R155K, and A156S or T or N) that were no longer detectable by population nucleotide sequencing at 6, 18, 24 and 36 months with the caveat that the follow-up data were limited and incomplete. Variants expressing one or more telaprevir substitutions remained detectable (i.e., present at >25% of the viral population) in some subjects at 24 months. By 36 months, V36M, T54S or A, and A156S/T/N variants had fallen below the level of detection in all subjects. Three percent of the subject isolates that had the R155K variant still had detectable R155K variants by population sequencing at 36 months. Lack of detection of a substitution based on a population-based assay does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment.
Figure 4: Persistence of Telaprevir Resistance-Associated Substitutions in Study 112: Percentage Wild-type (Months after Post Nadir Visit)
In addition, the viral populations of subjects failing a telaprevir-containing regimen in Studies 108, 111, and 216 were assessed at multiple time points after treatment-failure by population nucleotide sequencing to determine if the telaprevir-resistant variants initially present at the post-nadir visit were detectable in the viral population by the end of study (EOS) visit. Of the combined subjects from Phase 3 studies with a total of 443 resistant variants, 176 (40%) had detectable resistant variants by population sequencing by EOS (follow-up range 5-71 weeks, median 45 weeks) and results for loss of variants were similar across the three studies. In the combined studies, 50% of these substitutions in subtype 1a and 20% of the substitutions in subtype 1b were still detected by the EOS.
Figure 4: Persistence of Telaprevir Resistance-Associated Substitutions in Study 112: Percentage Wild-type (Months after Post Nadir Visit)
---------------------------------------------------------
LabCorp Introduces HCV Resistance Testing Through Monogram Biosciences With The Launch Of HCV GenoSure® NS3/4A
press release 08/25/11
Laboratory Corporation of America ® Holdings (LabCorp ®) (NYSE: LH) announced today the nationwide availability of a nucleic acid sequencing assay that reports NS3 and NS4A mutations and NS3 associated resistance to the recently approved hepatitis C virus (HCV) protease inhibitors, adding to LabCorp's suite of HCV testing. Identification of certain mutations may be useful to clinicians considering patient treatment decisions.
"HCV GenoSure NS3/4A represents the first in a series of HCV drug resistance assays that have been developed at Monogram Biosciences to support the clinical evaluation of HCV direct-acting antiviral (DAA) agents and their use in the management of HCV infection," commented Chris Petropoulos, PhD, LabCorp's Vice President of Monogram Research & Development. "We look forward to expanding our broad HCV assay portfolio to support the development and clinical application of additional DAA agents that target other distinct steps in the HCV replication cycle."
HCV GenoSure NS3/4A is currently available exclusively through LabCorp and its Monogram Biosciences Center of Excellence. The test is available for commercial use as well as clinical trial use. Monogram is an established leader in anti-viral drug resistance with 15 years experience in virology and infectious disease testing.
An estimated 3.2 million people in the United States and up to 170 million people worldwide are infected by HCV. Since 2002, the standard of care for HCV infection in the US has been treatment with pegylated α-interferon and ribavirin. In May 2011, the FDA approved the first two DAA agents, boceprevir (Victrelis, Merck & Co) and telaprevir (Incivek, Vertex Pharmaceuticals). Either agent is used in combination with pegylated α-interferon and ribavirin for the treatment of HCV genotype 1 infection. During clinical trials conducted to support regulatory approval, HCV variants containing mutations that confer reduced susceptibility to boceprevir and telaprevir emerged in patients who experienced sub-optimal treatment response.
HCV GenoSure NS3/4A analyzes the genetic sequence for the non-structural proteins NS3 and NS4A of HCV genotypes 1a and 1b that encode for an enzyme essential to viral replication. The assay detects mutations in NS3 and NS4A and specifically identifies those associated with boceprevir and telaprevir resistance.
Recommendations recently developed by the HCV Drug Resistance Advisory Group emphasize the value of resistance testing at treatment baseline and failure in support of the development and clinical evaluation of new drug candidates. In HIV, the routine use of resistance testing to guide antiviral drug treatment is established in clinical practice. In response to the recent and future availability of DAA agents, some experts anticipate that drug resistance testing will provide similar value to the clinical management of HCV infection.
About LabCorp®
Laboratory Corporation of America® Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.0 billion in 2010, over 31,000 employees worldwide, and more than 220,000 clients, LabCorp offers a broad test menu ranging from routine blood analyses to reproductive genetics to DNA sequencing. LabCorp furthers its scientific expertise and innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc., The Center for Esoteric Testing, Litholink Corporation, Genzyme GeneticsSM*, DIANON Systems, Inc., US LABS, Monogram Biosciences, Inc., and Esoterix and its Colorado Coagulation, Endocrine Sciences, and Cytometry Associates laboratories. LabCorp conducts clinical trials testing through its Esoterix Clinical Trials Services division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our Web site at: www.labcorp.com.
*Genzyme Genetics and its logo are trademarks of Genzyme Corporation and used by Esoterix Genetic Laboratories, LLC, a wholly-owned subsidiary of LabCorp, under license. Esoterix Genetic Laboratories and LabCorp are operated independently from Genzyme Corporation.
This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2010, and subsequent SEC filings.
|
|
| |
| |
|
|
|
