IL28B Results

[SusieS2010]

My IL28B results are no surprise. I am a TT. Can anyone explain how that test will impact treatment with the protease inhibitors?  I understand the meaning of the results for SOC but will adding a protease inhibitor change anything?

[eureka254]

Hi Susie,

Sorry that your results weren't more encouraging, but you've got a good attitude about it, that's for sure.  From the recent Vertex data submitted to FDA on Tele, the SVR rates for TT's varied from 73% to 57% for naives and treatment-experienced respectively.

If you want to pore over more details, it's on pp 10-11 of the submission:

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm252559.htm

(borrowed the link from willing) ~eureka

[HectorSF]

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm252559.htm

Pages 84-85

6.8 SVR by IL28 Genotype IL28B polymorphisms are linked to differences in SVR rates in HCV treatment naive subjects treated with Peg-IFN/RBV. The relationship between IL28B genotype and SVR in telaprevir-based therapy was investigated retrospectively in a subset of subjects who enrolled in studies C216 and 108. This analysis was not updated using the criteria described in Section 6.2.1.4.
Enrolment of the Phase 3 studies commenced prior to the discovery of IL28B. In Study 108, IL28B genotype was determined in de-identified left-over specimen available from
treatment-naïve genotype 1 HCV patients. In Study C216, patients who consented to genetic testing were included in a sub-analysis which evaluated virologic response by IL28B gentotype.
The racial distribution of subject samples used in these analyses from Study C216 (white
[94%], black [4%]) and Study 108 (white [100%]) were different because of sample deidentification requirements in Study 108, which allowed only samples from white subjects to be tested. Subjects had IL28B genotypes of CT (61% and 49%), CC (18% and 33%), and TT (21% and 18%) in studies C216 and 108, respectively. Distribution of IL28B genotypes in treatment-naïve patients in Study 108 was consistent with previously published results
(Ge D, et al. Nat 2009; 461:399-401)
Samples from 42% (454/1088) of Study 108 patients were available in the IL28B dataset;
and samples from Study C216 were available for 80% (527/662)
In Study C216, the highest proportion of IL28B TT subjects was among prior null responders
(28%) whereas the highest frequency of CC subjects was among prior relapsers (27%).
Differences in SVR rates among IL28B CC, CT and CC subjects were only evident when the
three subject subpopulations were pooled; however, SVR among CT and TT subjects were
still high (Table 20). Thus, in this retrospective analysis, IL28B genotype did not contribute
to outcome prediction in prior treatment-failure subjects treated with a telaprevir-based
regimen.
In Study 108, SVR rates in the IL28B dataset were comparable to the overall SVR rates in
Study 108 Caucasian patients (T12/PR: 78%, T8/PR: 65%, Pbo/PR: 38%) as well as in
overall Study 108 patients (T12/PR: 75%, T8/PR: 70%, Pbo/PR: 46%). In Study 108,
telaprevir-based therapy more than doubled the rates of SVR in CT/TT subjects, and
increased SVR rates in subject with CC genotype, compared with PR therapy alone
(Table 21). Non-attainment of eRVR was associated with lower SVR rates across all IL28B
genotypes, with the largest decrement in CT/TT subjects.

(See Charts for full breakdown)

Good luck!
Hectorsf

[SusieS2010]

Thank you so much for posting this information. Eureka, you saved me many hours of searching that 147 page document last night and I was able to sleep with a little hope.

Hector, your piece gives me even more hope. I was leaning toward not trying again since I read that only 13% of patients who were null-responders cleared the virus. I appreciate that you led me to later stats that actually broke previous treatment patients down into non-responders, etc. And the rate of SVR was, while not great, a lot better than I thought.

Thanks to both of you and have a great weekend.

[willing]

the most informative summary for your question seems to be Table 20 on page 85 of that long 147-page Vertex submission. IL28B status and prior treatment response are definitely not independent effects : among TTs for which data was available 16% were relapsers, 19% partial responders and 28% null responders. A pretty clear trend. On the other hand whether IL28B status contributes any additional predictive power over prior tx history seems doubtful, as emphasized in the Po et al EASL'11 presentation and in the FDA staff review comments quoted by Hector. When you look down the rows of table 20, there's no consistent trend between CC, CT and TT for each prior tx column.

I haven't done an il28b - measuring ifn response directly early in tx, pre-PI, seems a much more direct answer to the question.  All the best with your plans: that 13% number looks suspect - even among prior nulls triple tx reached 30s.

[dointime]

Thanks for posting your results.  I want to take this test too before I tx again.

Others have probably given better answers to your question but my unscientific understanding is this.  The PI will mow down your wild type virus but any resistant mutations will have to be dealt with by the SOC part of the triple combo.  As you understand the meaning of the result for SOC then that's your answer.

Best wishes,
dointime  

[GINGERPAL]

I am also TT result from my recent IL28B test.  I treated with SOC treatment in 2008, but stopped after 12 wks .  Below are my VL results from when I treated.
First time treating with Pegasys 180 mcg weekly and Ribavirin 1000 mg daily:  
Pre tx VL =   2.8 million IU =   6.453 log
2 wk post tx VL =  136,000 IU = 5.134 log
4 wk post tx VL =    10,900 IU = 4.037 log
8 wk post tx VL =        270 IU  = 2.43 log
12 wk post tx VL =        20 IU = 1.30 log
I am wondering if there is any way to tell what my changes of SVR will be with new Protease Inhibitors.
thanks.

[willing]

ginger: that looks like a very promising VL decline curve - many Drs would have continued past w12, possibly with dose adjustment/extension. In general, where prior tx information is available,  it trumps il28b status : the record of what the ifn actually did is more informative than the genetically-based prediction of what it might do. You had over a  2.4 drop during the equivalent of the 4w lead-in -  a promising ifn response. Though technically not a 'relapser' since you didn't pursue this for 48w it looks like you can plan on relapser-like odds : 80s and above.

susie: I realized the language in my post above is misleading, though the numbers are right. A clearer/more correct statement would be "among relapsers, partial responders and null responders, the percentage of TTs increased as 16% . 19% and 28%". Again, it's not that IL28B status is irrelevant, but prior tx history already includes your DNA biases and more.

dointime: agree with your point in an earlier post that if you're seeing any vl increase during triple tx, even as early as w4, you're almost certainly looking at replication of selected  PI-resistant virus. However an interesting twist from the FDA  submissions was that as many as 2.7% of pts could have a PI resistant variants at baseline - basically PI non-responders.  

[GINGERPAL]

Thanks Willling for your encouraging response -  I have been concerned about my IL28B "TT" result, but now feel better knowing that my 2.4 viral load drop is a good indicator.  It seems you are saying that  I did somewhat respond to the Interferon.  And with the new PI added to the mix....hopefully, I will have a decent chance.  I have been worried since getting the IL28B "TT" , and I am getting older, and think this may be my last chance to try.  

[dointime]

Yes, I agree.  The resistant variants can exist in the quasispecies before tx or they can evolve during tx with a PI.  

I suspect I already had a diverse quasispecies full of variants before tx as some of them figured out how to survive the PI as early as day 15.  I haven't read any studies on this but it stands to reason that having the virus for a long time might give it more of a chance to produce diverse mutations.  I would have thought that this would be the case for a lot more than 2.7% of pts.

If only there was a test sensitive enough to pick up resistant variants at baseline then a person could know that if they were a PI non-responder and an ifn non-responder then their chances with the triple therapy would not be good.

dointime          

[somuchmore2]

I am TT too. My is that CC could be force into current treatment first due to expense. Meaning if CC has not been treated yet then insurance companies will want to take Standard/Current Treatment first.

CT & TT would have better chance for approval because current treatment is so unsuccessful.

Oh well that is how I am thinking at this point.

Question:

How long will the lines be at doctors offices by June 1st if FDA approves on May 23rd. And, what can we expect supply chain availablility to be?

[SusieS2010]

We were told at the last Vertex meeting that they were setting up to make metric tons of the drug. So hopefully no one will have to wait.

Thanks for your explanation willing (and others). My best drop was with peg & riba and it was a 1.9 log drop at week 12. I will try telaprevir though as we don't know all the variables that make up the study participants. My NP assures me that she has seen people respond and surprise her many times. For me, the bottom line is, I have to know that I have tried everything available to me to try and get rid of this virus.

[dointime]

When you got to go, you got to go.  Best of luck with your tx.  When were you thinking of starting?  Let us know how it goes,

dointime