Replies to post #29137 on Biotech Values

[DewDiligence]

VX-950 CC post-mortem:

PROVE-1 and PROVE-2, which can logically be viewed as one study in two pieces, constitute one of the most complex trial designs I’ve ever seen in a phase-2 study in any indication. The analysts on the CC had to ask numerous questions about the rationale for the trial design, which was not always apparent even after the carefully worded explanations

Clearly, the company’s hope is that the treatment outcomes will be sufficiently phenomenal to enable an NDA to be submitted in 2007 based on phase-2 data. Whether this can in fact be done is unclear, but you can’t fault VRTX in planning for it.

[DewDiligence]

VX-950 trial-design notes from VRTX’s GS conference:

Because the GS webcast was mostly Q&A, there was a lot of color on the design parameters of the phase-3 VX-950 trials. There are three main cases, depending on what happens in the phase-2b trials called PROVE-1 and PROVE-2 (#msg-11248731), which together are testing 580 treatment-naïve, genotype-1 patients:

1. If the SVR rate after 3 months of 950+ifn is <65%, Boger will be disappointed and VRTX will probably have to drop the idea of stopping VX-950 after only three months. In this case, the phase-3 trials will almost certainly include one or more arms that test 950+ifn (and perhaps ribavirin) for at least 6 months.

2. If the SVR rate after 3 months of 950+ifn is >=85%, Boger will be delighted and VRTX will probably forego trying to get the SVR rate even higher by testing 950 treatment for longer than 3 months. In this case, the phase-3 trials will effectively become safety trials rather than efficacy trials and they will include a SoC arm only to the extent needed to establish that 950+ifn is as safe as SoC for a 3-month duration.

3. If the SVR rate after 3 months of 950+ifn is >=65% and <85%, Boger will be neither disappointed nor delighted and VRTX will have to include manifold arms in the phase-3 trials to ferret out the optimal treatment regimen. In this case, the phase-3 trials will compare the efficacy of 3 months of 950+ifn vs 6 months of 950+ifn. The role of ribavirin and the use of SoC following 3 months of 950+ifn remain open questions.

Dew

[DewDiligence]

Here are the VX-950 excerpts from VRTX’s
3Q06 PR. The most interesting near-term item
is that initial data for the first 80 patients in
PROVE-1 will be released in December. These
data will presumably be the 10-week evaluations
of the 60 patients on VX-950 for 12 weeks and
the 20 patients on SoC in the initial 80-pateint
randomization. (Note that AASLD will not have
data from any of the phase-2 VX-950 studies.)

http://biz.yahoo.com/prnews/061026/neth026.html?.v=67

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* The global Phase 2b clinical development program for telaprevir (VX-950) is advancing according to plan. In September, the Company announced that it had completed enrollment in the 260-patient PROVE 1 clinical trial. Vertex expects that the first data from the PROVE 1 clinical trial will become available in December 2006. These data will reflect an analysis of the safety and antiviral activity of telaprevir (VX-950) in 80 patients initially randomized to receive either 12 weeks of telaprevir (VX-950) therapy in combination with pegylated interferon and ribavirin, or 12 weeks of pegylated interferon, ribavirin and placebo.

* Vertex has initiated in Europe the 320-patient PROVE 2 clinical trial. The trial is on track to complete enrollment in the fourth quarter. The Company expects the first data from PROVE 2 to be available in mid-2007.

* The Company remains on track to initiate in the fourth quarter the PROVE 3, 400-patient clinical trial of telaprevir (VX-950) in patients with HCV who have failed prior treatment.

* Preliminary analysis including histopathology data from the six-month nonclinical studies with telaprevir (VX-950) in two species has been completed. Vertex believes these nonclinical studies will support clinical trials as planned. Complete reports will be provided to regulatory agencies in the fourth quarter.

* In September, Vertex announced that it has successfully completed the technical development work for the Phase 3 and commercial formulation of telaprevir (VX-950). With this formulation, the dosing of telaprevir (VX-950) is planned as two 375 mg tablets to be taken every eight hours. Vertex has begun to manufacture drug substance registration batches and all registration batches are anticipated in the first half of 2007. Vertex expects to make a significant investment in the commercial supply for telaprevir (VX- 950) in 2007, subject to continued progress of the drug candidate.
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[DewDiligence]

Telaprevir Attains 61-65% SVR in Phase-2 HCV Trials

[These SVR rates are much better than the interferon + ribavirin standard of care, but they fall short of the lofty expectations that VRTX has sowed for Telaprevir (formerly VX-950) during the past two years, IMO. The 61-65% SVR rates are ITT numbers from the 24-week treatment arms (12 weeks of Telaprevir+SoC and 12 weeks of SoC alone) from the two phase-2 trials in treatment-naïve HCV known as PROVE-1 and PROVE-2; these data are being presented at the AASLD conference that starts today. For details of the various arms in PROVE-1 and PROVE-2, please see #msg-11248731. VRTX’s own PR can be read at:
http://biz.yahoo.com/bw/071102/20071101006689.html?.v=1 .]

http://www.reuters.com/article/marketsNews/idUKN0145229320071102

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Fri Nov 2, 2007 1:00am EDT

BOSTON, Nov 2 (Reuters) - Vertex Pharmaceuticals Inc's (VRTX) experimental hepatitis C drug is more effective than existing treatments and works in half the time, but also causes significantly more side effects.

Data being presented at the Annual Meeting of the American Association of the Study of Liver Diseases show the drug, telaprevir, in combination with standard treatment, eradicated the hepatitis C virus in more than 60 percent of patients who took it as part in a 24-week treatment.

Eradication of the virus is based on a measure known as sustained viral response, in which the virus remains at below detectable levels.

Typically, not more than 50 percent of patients taking standard treatments see their virus eradicated and the typical length of treatment is 48 weeks.

In a mid-stage trial conducted in the United States known as PROVE 1, 61 percent of 79 patients who took telaprevir in combination with the standard treatments, pegylated interferon and ribavirin, saw the virus fall to undetectable levels in their blood and remained undetectable six months after treatment was stopped. [This is the definition of SVR.]

But 13 percent of patients discontinued the trial in the first 12 weeks because of side effects. The most common side effect was rash.

In a separate mid-stage trial known as PROVE 2, conducted in Europe, 65 percent of patients who took part in the 24-week treatment regime -- which consisted of 12 weeks of triple therapy followed by 12 weeks of standard treatment – saw the virus eradicated and stay eradicated after six months.

In the PROVE 1 trial, the relapse rate was 2 percent. In PROVE 2 it was 14 percent. Patients who take standard therapy typically relapse at a rate of 20 percent to 30 percent, Vertex said. The difference in relapse rate between the two trials stemmed from the fact the PROVE 1 trial results were based only on patients who were least likely to relapse in the first place, based on the rapidity of their initial response to the drug. [The above explanation is confusing—please see #msg-11248731 for a clearer explanation of the differences between PROVE-1 and PROVE-2.] In the PROVE 2 trial, which did not just measure patients who saw a quick drop in virus after starting therapy, 14 percent of patients relapsed.

Telaprevir is one of a new class of drugs that inhibits a hepatitis C protease, an enzyme essential for the virus to replicate. Vertex's partner on the drug is Tibotec Pharmaceuticals Ltd, of Cork, Ireland [a subsidiary of JNJ].
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[DewDiligence]

VRTX Reports Final Data from PROVE-1/2 Trials in Treatment-Naïve HCV

[Actually, these data are not quite final because SVR12 rather than SVR is reported for the control arm in PROVE-2. In all other respects, the data are final. Although nothing in this PR materially changes the data from PROVE-1 and PROVE-2 that had already been disclosed to investors, the aggregate dropout rate in all Telaprevir arms was 17% — a bit higher than some investors expected, judging by the downturn in the price of VRTX shares on Wednesday. Note: PROVE-1 and PROVE-2 were similar trials but not exact clones; please consult #msg-11248731 for the precise trial deigns.]

http://biz.yahoo.com/bw/080423/20080423005213.html

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Telaprevir-Based PROVE Studies Show Significantly Higher SVR Rates in Treatment-Naive Genotype 1 Hepatitis C Patients in Half the Time of Current Treatments

Wednesday April 23, 8:00 am ET

- High sustained virologic response (SVR) rates of 61% in PROVE 1 and 68% in PROVE 2 with 24-week telaprevir-based treatment regimen -

- Telaprevir first and only investigational HCV protease inhibitor in Phase 3, ADVANCE trial underway -

MILAN, Italy--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX ) today announced data from two large Phase 2b clinical trials evaluating the investigational hepatitis C virus (HCV) protease inhibitor telaprevir (VX-950), dosed in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) in treatment-naïve, genotype 1-infected HCV patients. Final results from PROVE 1 and further interim analysis from PROVE 2 showed consistently higher SVR rates and antiviral response in the 24-week telaprevir arms -- 61% of patients in PROVE 1 and 68% of patients in PROVE 2 achieving SVR, compared with 41% of patients in the PROVE 1 control arm achieving SVR and 48% of patients in the PROVE 2 control arm having undetectable HCV RNA at 12 weeks post-treatment. These data will be presented at the 43rd Annual Meeting of the European Association for the Study of the Liver in Milan, Italy from April 23-27, 2008.

“Patients in the completed PROVE 1 study, and those thus far reported in an interim assessment of PROVE 2 who received a telaprevir-based regimen for 12 weeks, followed by 12 weeks of pegylated interferon and ribavirin, achieved SVR rates approximately 20% higher than the SVR 24 (PROVE 1) or SVR 12 (PROVE 2) seen in the 48-week control arms and demonstrated the potential of telaprevir to produce sustained viral responses in greater numbers of patients,” said John McHutchison, M.D., Principal Investigator for the PROVE 1 trial and Associate Director of the Duke Clinical Research Institute. “In the Phase 3 ADVANCE trial we will further evaluate the potential of telaprevir to increase SVR and shorten duration."

Low Relapse Rates Observed with 24-week Telaprevir-Based Regimens

In PROVE 1 and PROVE 2, a combined relapse rate of 5% (2% in PROVE 1 and 7% in PROVE 2) was reported in patients treated with a 24-week telaprevir-based treatment regimen who were undetectable at week 4 and week 12 (HCV RNA <10 IU/mL). In the 48-week control arms, a relapse rate of 23% was observed in PROVE 1 at 24 weeks post-treatment and a relapse rate of 20% was observed in PROVE 2 at 12 weeks post-treatment. At the time of the analysis, only 12-week post-treatment relapse data were available for patients in the PROVE 2 control arm. SVR calculations include some patients who did not complete the full course of therapy, and therefore are not included in the relapse rate calculation.

“In the treatment arms that included telaprevir, pegylated interferon and ribavirin, a high percentage of patients who had undetectable virus at week 4 and 12 developed a sustained viral response,” said Dr. Geoffrey M. Dusheiko, Investigator for PROVE 2 and Professor of Medicine at Royal Free Hospital and University College London Institute of Hepatology. “If these results are validated in Phase 3 studies, shorter courses of treatment for a larger percentage of treatment-naïve hepatitis C genotype 1 infected patients may be possible.”

Telaprevir Safety & Tolerability Consistent with Prior Analyses

In Phase 2 clinical studies to date, more than 700 patients have received a telaprevir containing regimen, and the adverse event profile is generally consistent across studies and prior analyses. In the PROVE 1 and PROVE 2 studies, telaprevir is being evaluated in combination with Peginterferon alfa-2a and Ribavirin for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1. In these placebo-controlled studies, the most common adverse events reported more frequently in the telaprevir treatment arms compared to the placebo arms were gastrointestinal events, skin events (rash, pruritus) and anemia. Other adverse events reported were similar in type and frequency to those seen currently with peg-IFN/RBV treatment.

Treatment discontinuation rates in the combined data through week 24 of treatment due to adverse events were 17% in the telaprevir treatment arms. In the control arms, 10% of patients discontinued treatment during the 48-week treatment period. The most common adverse event leading to discontinuation in the telaprevir arms was rash in 7% of patients across both PROVE 1 and PROVE 2. Investigators have reported that the rash resolves upon discontinuation of telaprevir.

Telaprevir Data Presentations at EASL Meeting

Oral Presentations:

“PROVE 1: Results From a Phase 2 Study of Telaprevir with Peginterferon alfa-2a and Ribavirin in Treatment-Naïve Subjects with Hepatitis C,” on Thursday, April 24th at 3:45 p.m. CEST (9:45 a.m. EDT).

“Treatment of Chronic Hepatitis C with Telaprevir (TVR) in Combination with Peginterferon-alfa-2a with or without Ribavirin: Further Interim Analysis Results of the PROVE2 Study,” on Friday, April 25th at 11:45 a.m. CEST (5:45 a.m. EDT).

Late-Breaker Poster Presentation:

"A Study of Telaprevir (TVR) with Peginterferon alfa-2A (P) and Ribavirin (R) in Subjects with Well-documented Prior P/R Null Response, Non-Response or Relapse: Preliminary Results" starting on Thursday, April 24.

Poster Presentation:

“Natural Prevalence Of HCV Variants with Decreased Susceptibility to NS34a Protease Inhibitors in Treatment-Naïve Subjects,” starting on Thursday, April 24.

About PROVE 1 and PROVE 2

PROVE 1 is a four-arm, Phase 2b clinical trial of 250 treatment-naïve genotype 1 HCV patients with a primary objective to assess the proportion of patients who achieve SVR, defined as undetectable (less than 10 IU/mL, as measured by the Roche TaqMan® assay) HCV RNA 24 weeks after the completion of dosing. The study is assessing patients who receive telaprevir-based treatment regimens of 12, 24 and 48-week durations, compared to a 48-week control arm of pegylated interferon and ribavirin. PROVE 1 is being conducted at 37 clinical centers in the U.S.

PROVE 2 is an ongoing, four-arm, Phase 2b clinical trial of 323 treatment-naïve genotype 1 HCV patients with a primary objective to assess the proportion of patients who achieve SVR. The study is assessing patients who receive telaprevir-based treatment regimens of 12 and 24-week durations and a 12-week arm without ribavirin, compared to a 48-week control arm of pegylated interferon and ribavirin. PROVE 2 is being conducted at 28 clinical centers in Europe.

About Telaprevir and ADVANCE Phase 3 Clinical Development

Telaprevir (VX-950) is an investigational oral inhibitor of HCV protease, an enzyme essential for viral replication, and is the most advanced investigational agent in development that specifically targets HCV. Telaprevir is the first hepatitis C protease inhibitor in Phase 3 clinical development. The ongoing ADVANCE trial is a global, 3-arm pivotal controlled trial designed to evaluate two 24-week telaprevir-based regimens in approximately 1050 treatment-naïve genotype 1 HCV patients. In this study, extended RVR criteria (undetectable HCV RNA at week 4 and week 12) will be used to determine which telaprevir patients can stop all treatment at 24 weeks. In addition to ADVANCE, Vertex is conducting a global Phase 2b clinical development program of telaprevir, including PROVE 1 and PROVE 2 in treatment-naïve genotype 1 HCV patients, and PROVE 3 in genotype 1 HCV patients who have not achieved SVR with a prior course of pegylated interferon-based therapy. In these clinical trials, telaprevir is being dosed as 750 mg every eight hours in combination with pegylated interferon alfa-2a (Pegasys®) both with and without ribavirin (Copegus®).

Vertex retains commercial rights to telaprevir in North America. Vertex and Tibotec are collaborating to develop and commercialize telaprevir in Europe, South America, Australia, the Middle East and other countries. Vertex is collaborating with Mitsubishi Pharma to develop and commercialize telaprevir in Japan and certain Far East countries.
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