telaprevir and VX-222 phase 2 study

Vertex Broadens its Commitment to Improving HCV Care with Clinical Trial to Evaluate Combination Regimens Based on Oral Antiviral Therapies
-Trial will evaluate safety and SVR rates with multiple 12-week response-guided regimens of telaprevir/VX-222-based combination therapy, including two-drug regimens of telaprevir and VX-222-
-Interim clinical data expected in the second half of 2010-
-Multiple clinical trial sites in the U.S. to enroll patients-
CAMBRIDGE, Mass., Mar 01, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it is initiating the first clinical trial evaluating Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, dosed in combination with the company's lead investigational HCV polymerase inhibitor, VX-222. This Phase 2 trial will evaluate sustained viral response rates (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment) using multiple 12-week response-guided regimens of telaprevir/VX-222-based combination therapy, including two-drug regimens that contain only telaprevir and VX-222. The trial is expected to enroll approximately 100 treatment-naïve genotype 1 HCV patients at multiple clinical trial sites, the majority of which will be located in the U.S. Enrollment is expected to be completed in the second quarter of 2010. Vertex expects to obtain interim clinical data, including safety and viral kinetic data, from this trial in the second half of 2010.

"Vertex is committed to improving patient care in HCV, and the announcement of this clinical trial combining two oral agents, telaprevir and VX-222, signifies our first exploration into this combination regimen's potential role to further improve the treatment of HCV," said Peter Mueller, Ph.D., Vertex's Chief Scientific Officer and Executive Vice President, Global Research and Development.

"The completion of the Phase 3 development program for telaprevir remains our primary focus, and we are on track to submit a New Drug Application for telaprevir in the second half of 2010. We believe telaprevir could represent a significant opportunity to improve the treatment of HCV, and simultaneously, we are focused on evaluating additional opportunities to potentially enhance HCV therapy even more in the years ahead using novel combination regimens based on oral antiviral agents. We believe the trial announced today will inform the development path for telaprevir/VX-222-based combination therapy, and we look forward to obtaining the first clinical data from the trial later this year," continued Dr. Mueller.

About the Phase 2 Trial of Telaprevir and VX-222

The randomized, parallel-group, dose-ranging trial announced today is designed to evaluate the safety and antiviral activity, including SVR, of multiple 12-week response-guided telaprevir/VX-222-based combination regimens. The primary endpoint of this trial is to assess safety and tolerability of telaprevir/VX-222-based combination therapy. A secondary endpoint of this study is to assess the proportion of patients in each study arm who achieve SVR. The trial is expected to enroll approximately 100 treatment-naïve genotype 1 HCV patients at approximately 20 clinical trial sites, predominantly in the U.S. Vertex expects to complete enrollment for the trial in the second quarter of 2010. The trial will consist of four arms, as noted below:

12-Week Treatment Regimens Patient Enrollment
Telaprevir (1125 mg BID) + VX-222 (100 mg BID) 25
Telaprevir (1125 mg BID) + VX-222 (400 mg BID) 25
Telaprevir (1125 mg BID) + VX-222 (100 mg BID) + peg-IFN + RBV 25
Telaprevir (1125 mg BID) + VX-222 (400 mg BID) + peg-IFN + RBV 25
BID = twice daily, peg-IFN = pegylated interferon, RBV = ribavirin
Response-Guided Trial Design

The trial will utilize response-guided criteria aimed at evaluating shorter-duration treatment regimens. All patients, regardless of treatment group, whose HCV RNA levels are undetectable (<10 IU/mL) at week 2 and week 8 of treatment, will stop their assigned treatment at week 12. Patients who do not meet these criteria will complete their assigned treatment and at week 12, those in the dual-drug regimen will receive follow-on therapy of 24 weeks of pegylated-interferon (peg-IFN) and ribavirin (RBV), for a total of 36 weeks of treatment. Patients in the quad-therapy regimens who do not meet these criteria at week 12 will receive an additional 12 weeks of follow-on therapy with peg-IFN and RBV for a total of 24 weeks of peg-IFN and RBV therapy.

Potential Additional Arms of Telaprevir/VX-222-based Combination Treatment

Based on an evaluation of on-treatment safety, pharmacokinetic and antiviral data from patients in each arm of the trial, Vertex may elect to enroll up to two additional treatment arms that will evaluate telaprevir/VX-222-based combination therapy. The components of the treatment regimens of these arms will be selected based on clinical data that emerges from the four initially-studied regimens. If enacted, up to 25 patients are expected to enroll in each additional treatment arm.

Recent Clinical Trials Support Evaluation of Telaprevir/VX-222-based Combination Regimens

Phase 1b/2a Clinical Trial of VX-222 in HCV Patients

Interim clinical results from a two-part Phase 1b/2a clinical trial of VX-222 showed that in the multiple-dose Phase 1b viral kinetic portion of the trial (Part A), VX-222 was well-tolerated across four VX-222 dose groups with no serious adverse events reported. Part A enrolled 32 genotype 1 HCV patients to receive three days of dosing, and a mean HCV RNA decline of greater than 3 log10 was observed across all four VX-222 dose groups. An increasing dose response was observed across the four dose groups, with the results with 500 mg and 750 mg BID, and 1500 mg QD (once-daily) being very similar. The mean HCV RNA decline achieved after three days of dosing with 250 mg, 500 mg, and 750 mg of VX-222 every 12 hours (q12h) was 3.1 log10, 3.4 log10, and 3.2 log10, respectively. Additionally, the mean HCV RNA decline achieved after three days of dosing with 1500 mg of VX-222 every 24 hours (QD) was 3.4 log10. For patients who received placebo, the mean HCV RNA decline after three days of dosing was 0.1 log10. The majority of the patients enrolled in Part A had genotype 1a chronic HCV infection. Full results including the final safety analysis from Part A of this trial are expected to be presented at a medical meeting in 2010.

The interim results of Part A of this trial are consistent with the findings from a previously-conducted three-day, five-patient viral kinetic study of VX-222. Part B of the study, which will be initiated shortly will evaluate 12 weeks of VX-222 dosed in combination with peg-IFN and RBV in treatment-naïve HCV patients.

[robo229]

This certainly is encouraging news.  An all oral treatment without Interferon/Ribavirin seems ideal.  It's similar to the INFORM trial but with a drug that has more data and experience (Telaprevir).  

Maybe the Hep C community has learned something from the HIV model of a cocktail approach.

I would caution against getting overly excited from information from the business community.  It is often designed to encourage shareholders and other investors and can be misleading to the public and affected community (hep c patients) without the benefit of peer review.  Having said that, I'd still welcome the opportunity to enroll, especially given my prior inf/riba experience.

Robo

[burned74]

Thanks so much for this post. I was wondering when Vertex would make another statement regarding Teleprevir. it supposedly takes about a year for FDA approval after submission so it really does look like 2011 for Teleprevir.

I was stage 2 several years ago and I am getting a little older (52) so I will treat with SOC plus Teleprevir next year. I will probably look to add Alinia and do a lead in with ribi and a shorter duration between peg shots at the begining. Maybe every 5 days for the first month?

One word to the wise that I have gotten from this site about  protease and polyprotease inhibitor trials is if they fail, the HCV in that individual is now resistant to future treatments with inhibitors will not work. Several people here tried and failed without ribivirin and now they are screwed as they cant use teleprevir at all.

[robo229]

Just curious about your "word to the wise"

I've not heard that failing on a particular HCV protease inhibitor or polymerase inhibitor would eliminate a whole class of medications for future treatment.  Is this anecdotal from other posts on medhelp or is there a reference I can review?  I'd appreciate any further information on the subject.

Best,
Robo

[Rockerforlife]

Good point.i wouldnt do trail with the knowledge that without RIBA in the mix ,you may be shut out of the PI drugs mutation happens.you screwed big time,matbe is i was in the later stage of damage and desperate.

[Rockerforlife]

sorry for the mis typing...was in a hurry

[burned74]

I have seen several posts on this site stating that they had not cleared in a trial (one lady in particular blamed it on being in the no riba arm but there is no way to tell for sure) and they were later told by doctors that the HCV was now resistant to most (maybe all, I am not sure) protease inhibitors or polymerase inhibitors.

Obviously, you can't believe everything you read here but I have seen at least a couple people say this and have not not seen anything to the contrary.

[hobo2]

I don't know if this will be helpful, but from what I know about protease inhibitors, is that they really don't necessarily fail, in as much as continued use of of a certain inhibitor will eventually build up within a patient.  The fix to tolerances, is to simply stop taking them for a few days or simply jump over to another inhibitor with similar but different chemical structures.    The HCV is highly transmutable, meaning that it adapts and transforms it's genetic design to survive most attacks,  I read somewhere that HCV can mutate up to 1,000 times in a years time..   Don't know how true that is, but sounds about right to me.
Protease inhibitors basically stop the progression of inflamitory actions and prevents the spread or replication of a certain strain of virus, or viruses.   Take a deadly "Snakebite" for example, the poison from the Venom gets into the body, causes quick swelling at the bitten area, and spreads through the victims blood to eventually cause the persons death, if an "anti-venom" is not given in time enough.  The protease actions of the bitten area is basically the reactions of poisoning.  The "Inhibitor" is the chemical within a planet or drug, that stops the actions of the "Protease poisoning".    
  It might also be helpful to know that HIV and HCV closely resemble each other is actions, however, they only differ at the point of their protease responses, this is why often, a certain protease inhibitor will also be used in HIV cases too.  
~Not trying to sounds like I know about "all" the in's and out's of these things, but for what it's worth...these are a couple things that I've picked up along the information highway! :-}  
   Good health to you all, and God bless!

[WriteItDown]

Protease inhibitors can create resistant mutations in the HCV virus. Because the ones currently being studied exhibit overlap in the mutations created, it's believed that after failing treatment with one of them, a patient will also fail with another. This is not the case with polymerase inhibitors which do not create resistant mutations.

I believe the person you're referring to is Susan400, who was in the arm of the Telaprevir trial where they didn't get ribavirin. They know now that no riba doesn't work, because the people in that arm had much lower SVR rates than in the other arms.

[Bill1954]

Hi Robo—

Again anecdotal, and I’ll keep my eyes open for published stuff on this. I believe that PI resistance can occur when used as mono-therapy; however, IFN tends to clean up any ‘escape variants’ that might develop. I imagine ‘willing’ would have ready reference to this; it’s out there, I just don’t have any in my hard drive.

How are things going? I hope you’re doing well; keep us in the loop, my friend—

Bill

[WriteItDown]

Yes, protease inhibitors do create resistance during monotherapy, but unfortunately it can also happen during triple therapy.

[eureka254]

Not willing himself, but willing to help:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645896/?tool=pmcentrez

Also, searching the pubmed site with keywords "hepatitis c resistance teleprevir" will lead you into many related artiles (boceprevir, R7227, etc...)

Best wishes,
eureka

[Bill1954]

http://www.natap.org/2006/AASLD/AASLD_17.htm

“ …They used a highly sensitive clonal method to characterize the mutations (viral variants), and they also did a phenotypic analysis. VX-950 has demonstrated a rapid & profound viral load reduction; drug resistance mutations can emerge when VX950 is given alone (as monotherapy), as sequence changes (mutations) in the HCV genome occur spontaneously & frequently as a natural result of the high levels of replication of the HCV virus-pre-existing mutations are likely present at a low level prior to **************; but, resistant HIV and wild-type HCV (non-resistant virus) were suppressed & became undetectable with Pegasys added in combination therapy. With continued use of Pegasys+Ribavirin, after VX950 was stopped in the short-term study of VX950, wild-type & resistant HCV were suppressed & became or remained undetectable….”

Bill

[Bill1954]

Wow, thanks for referencing this article; I had no idea that naturally occurring variants were much of an issue. I’ll read more of this tomorrow when my eyes are open, but just skimming through, this caught my eye:

“Importantly, continued viral replication in the presence of the selecting drug would put the patient at risk to develop additional resistance mutations. Here, observations from HIV infection suggest that baseline resistance even against only one drug in a multidrug antiviral regimen may jeopardize treatment success (12), and further indicate that apart from single mutations conferring high level resistance, stepwise accumulation of subtle but synergistically acting resistance mutations may also eventually lead to treatment failure (30).”

Thanks again, Eureka—

Bill

[Willy50]

The thing that captures my attention about this trial is that the timetable for intent to treat is 12 weeks and all treatment stops. (based on UND at week 2 and 8)

Yes, if one responds slower or less completely it will be longer, but it appears to me that they feel that with the twin antiviral compounds will bring a sizable group to undetectable at 2 and presumably thru 8 weeks.

One can also infer that since undetectable at 12 weeks is not a criteria, that they expect that if one attains undetectable at 2 weeks, and holds that status for 6 weeks the virus is expected to be gone and stay gone, at least in a significant number of trial participants.  That is huge.  We will soon (ha; in over a year!) see if it proves to be true.

Vertex recently said that they expected that they could provide about an 8 log reduction with the two compounds (I assume that could be an average).  I didn't catch it expressed but I assumed that referred to the two compounds, not the twin PI's combined with IFN and RBV.  That is crazy stuff; an 8 log drop in 2 weeks!!!  One assumes that they were referring to an 8 log drop in two weeks since that is the early cut off in the trial.

Regarding the mixing of the two PI's, or the combining with IFN and RBV......

Since each compound may cover a certain number of strains of virii, the more compounds used the greater the likelihood of wiping out the virus before it can mutate.

Over time they may develop a system of closely monitoring the viral decline and adjusting dosing.  They may be able to tell after a person is exposed to Telaprevir and VX-222 that the recipient isn't experiencing a quick enough viral reduction and may simply add SOC.  I would venture a guess that response rates could be extrapolated in a very short period of time.  Therefore, even slower responders could experience a complete response in a short period of time.  As seen in other threads they are also beginning to dial in the genetics of response and may also have a handle on what type of TX one will require even before one treats.

The somewhat scary part of this trial may be that any participants could become resistant, as a few members of this forum have already experienced.

The wonderful thing about this trial is that even  a person who had prior failed in a TVR trial, and who may possess resistant virii to Telaprevir, well...... this is a type of TX which could very well cure them.
  The monotherapy viral decline for TVR was about 3.5, tops in 2 weeks.  Usually that happened in the first week.  One has to wonder if the 2 PI's can provide about an 8 log drop in the same period of time whether this will be sufficient to overcome any and all resistant virii, possibly with or without IFN and RBV.

It's all speculation at this point of course, but very exciting and promising.

By the way..... one other very cool thing about this trial is that for some people...... they will be done treating in 12 weeks, have an official SVR in 24 weeks; =3/4 of a year.

Since the entire duration of a trial will start at the first dose and end presumably 6 months after the last person doses this trial won't be truly complete until the last 36 week patient doses plus the 24 week/ 6 month EOT PCR.

The 2 potential additional arms that could be enacted will also slow the end result but will provide a means of further correcting/ or improving the trial, on the fly so to speak.

Anyway..... this is tremendously interesting to me and a potential boon for all of us.

Willy