Replies to post #68108 on Biotech Values

[DewDiligence]

Yesterday’s Telaprevir PR for archival
purposes—the prior PR’s from which to
determine what’s new are as follows:

PROVE-3: #msg-29896176
*PROVE-2: #msg-28746843
‘107’ study: #msg-28749322
C208 study: #msg-33270634

*Final data except that control arm had SVR12 instead of SVR.

http://biz.yahoo.com/bw/081101/20081101005015.html

›New Clinical Data Support Broad Profile for Telaprevir in Patients with Genotype 1 Hepatitis C Virus (HCV) Infection

Saturday November 1, 11:00 am ET

-- PROVE 3 data show 52% SVR12 in HCV treatment-failure patients with 24-week treatment duration --

-- PROVE 2 final results confirm 69% SVR in HCV treatment-naive patients with 24-week treatment duration --

-- C208 study interim analysis supports potential for future twice-daily telaprevir dosing --

SAN FRANCISCO--(BUSINESS WIRE)--New clinical data from four Phase 2 clinical trials of the investigational hepatitis C protease inhibitor telaprevir (VX-950) to be presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco support a broad profile for telaprevir in the treatment of chronic genotype 1 hepatitis C virus infection. Telaprevir is being developed by Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX ) in collaboration with Tibotec.

“Data from Phase 2 telaprevir clinical studies in genotype 1 HCV patients are encouraging as responses were seen in treatment-naïve patients, as well as in those who had previously failed treatment with the current standard of care regimen," said John McHutchison, M.D., Principal Investigator for the PROVE 3 study and Associate Director of the Duke Clinical Research Institute. "PROVE 3 data showed that a telaprevir regimen produced a 52% SVR12 in treatment-failure subjects, which is noteworthy as patients who have failed therapy are very difficult to manage due to limited available treatment options and are at greater risk for developing progressive liver disease."

"The data being presented at AASLD support the potential for telaprevir to have a broad role in genotype 1 HCV patients, including those naïve to treatment and those who have previously failed one or more courses of pegylated interferon and ribavirin,” said Freda Lewis-Hall, M.D., Executive Vice President, Medicines Development at Vertex. “In addition to the positive data seen in treatment-failure patients, in the final results from PROVE 2 we see the potential for a significant proportion of treatment-naïve genotype 1 HCV patients to achieve SVR with a 24-week telaprevir-based regimen.”

PROVE 3 Interim Analysis for Patients Who Failed to Achieve SVR with Prior Therapy

The PROVE 3 data show a 52% SVR12 in HCV treatment-failure patients, with a 24-week treatment duration. Results are an interim analysis of a Phase 2b randomized, double-blind, placebo-controlled study in 453 patients who failed prior treatment with pegylated-interferon (peg-IFN) and ribavirin (RBV), including non-responders, prior relapsers and prior breakthroughs. PROVE 3 patient dosing was completed earlier this year and all patients are currently being followed post-treatment.

A summary of PROVE 3 antiviral response rates in one of two 24-week telaprevir-based treatment arms (12 weeks telaprevir in combination with peg-IFN/RBV, followed by 12 weeks peg-IFN/RBV only) categorized by patients’ prior response to peg-IFN/RBV treatment is presented below.

PROVE 3 Treatment Arms

Interim Undetectable HCV RNA (<10 IU/mL) in PROVE 3 24-week regimen
(intent-to-treat analysis)
SVR12(4)

Non-responders (n=66)(1)
41% (27 of 66)

Relapsers (n=40)(2)
73% (29 of 40)

Breakthroughs (n=9)(3)
44% (4 of 9)
Total (n=115) 52% (60 of 115)


[1] Non-responders are defined as patients who never achieved undetectable HCV RNA during prior therapy.

[2] Relapsers are defined as patients who achieved undetectable HCV RNA at the completion of prior treatment, but relapsed during post-treatment follow-up.

[3] Breakthroughs are defined as patients who had undetectable HCV RNA during prior treatment, but had detectable HCV RNA before the end of prior treatment.

[4] SVR12 = undetectable HCV RNA (<10 IU/mL) measured at 12 weeks post-treatment.

In the PROVE 3 control arm (48 weeks of peg-IFN/RBV), 30% (34 of 114) of patients had undetectable HCV RNA at week 36 on treatment (intent-to-treat analysis). At week 12 on treatment, 8% of these patients (9 of 114) had undetectable HCV RNA.

Study 107 Interim Analysis in Treatment-Failure Genotype 1 HCV Patients

In Study 107, a separate study of telaprevir-based regimens in well-characterized treatment-failure patients, researchers found that a high proportion of these patients had a rapid viral response and maintained undetectable HCV RNA (<10 IU/mL) through 24 weeks of treatment, further supporting the role for telaprevir in the treatment-failure population. A large number of patients enrolled in Study 107 had prior null-response. Interim efficacy results include data for patients who have reached respective visits or who had discontinued therapy for any reason or who became detectable at each timepoint. These interim results from Study 107 are summarized in the table below.

Prior Virologic Response in Phase 2 PROVE control arm Studies(1)


Interim Undetectable HCV RNA (<10 IU/mL) by Response to Prior Peg-IFN/RBV Treatment at Week 4, 12 and 24(1)
Week 4 Week 12 Week 24

Null-responder (n=48)(2)
40% (19 of 48) 61% (28 of 46) 43% (18 of 42)

Partial responder (n= 33)(3)
85% (28 of 33) 90% (26 of 29) 82% (18 of 22)

Relapsers (n= 22)(4)
91% (20 of 22) 94% (16 of 17) 83% (5 of 6)

Breakthrough (n=1)(5)
100% (1 of 1) 100% (1 of 1) 0% (0 of 1)


[1] Patients are unique in each of the non-response categories.

[2] Null-responders defined as patients who had less than a 1 log(10) decrease in HCV RNA at week 4 or less than a 2 log(10) decrease in HCV RNA by week 12.

[3] Partial-responders defined as patients who had a greater than or equal to 2 log(10) decrease in HCV RNA at week 12, but had detectable HCV RNA at week 24.

[4] Relapsers defined as patients who had undetectable HCV RNA at the end of treatment, but reverted to detectable levels of HCV RNA during follow-up.

[5] Breakthrough defined as patients who had detectable HCV RNA after achieving undetectable HCV RNA during treatment with standard therapy.

The Study 107 results presented at AASLD represent an interim analysis of the ongoing, open-label Phase 2 study designed to evaluate telaprevir in patients who failed to achieve SVR in the 48-week control arms of the Phase 2 PROVE studies. In Study 107, at entry patients had been well-characterized as null responders, partial responders, relapsers or breakthroughs to prior peg-IFN and RBV treatment as a result of their participation in a prior Vertex PROVE clinical trial. The analysis includes data from all 104 patients enrolled in Study 107 who received at least one dose of study drug and who completed at least the Week 4 assessment. Patients continued treatment at week 4 and 12 if they did not meet the stopping rule criteria, defined as HCV RNA >100 IU/mL and HCV RNA >25 IU/mL (Roche Taqman assay, version 2.0) at week 4 or 12, respectively.

PROVE 2 Final Results in Genotype 1 HCV Treatment-Naïve Patients

PROVE 2 final results confirm 69% SVR in HCV treatment-naïve patients with 24-week telaprevir-based treatment durations. A more detailed summary of final intent-to-treat SVR rates from PROVE 2, a study of 323 genotype 1 treatment-naïve patients, is presented below.

PROVE 2 Treatment Arms SVR %
24-week telaprevir treatment arm 69% (56/81)
12 weeks telaprevir/peg-IFN/RBV,
followed by 12 weeks peg-IFN/RBV
12-week telaprevir treatment arm with ribavirin 60% (49/81)
12 weeks telaprevir/peg-IFN/RBV
12-week telaprevir treatment arm without ribavirin 30% (28/78)
12 weeks telaprevir/peg-IFN
48-week control arm 46% (38/82)
48 weeks peg-IFN/RBV

Safety and Tolerability Across PROVE 3, Study 107 and PROVE 2

In Phase 2 clinical studies to date, more than 1,000 patients with genotype 1 HCV have received a telaprevir-containing combination regimen, and the adverse event profile is generally consistent across studies and prior analyses. In the PROVE 3, Study 107 and PROVE 2 telaprevir studies, the most common adverse events reported more frequently in patients receiving telaprevir were gastrointestinal events, skin events (rash, pruritus) and anemia. There have been reports of severe rashes in clinical studies of telaprevir-based therapy. Other adverse events reported were similar in type and frequency to those reported with peg-IFN and RBV treatment.

In the PROVE 3 interim analysis, 16% of patients in the telaprevir-based treatment arms discontinued due to adverse events prior to week 36, while 4% of patients in the 48-week control arm discontinued treatment in the same time period. Rash was the most common reason for discontinuation in 6% of patients. In the Study 107 interim analysis, 8% of patients discontinued due to adverse events. The most common reason for discontinuation was rash in 4% of patients. In the PROVE 2 final analysis, 14% of patients receiving a 24-week telaprevir-based treatment regimen discontinued all study drugs due to adverse events, compared to 7% in the 48-week control arm. The discontinuation of all treatment in the telaprevir-based treatment arms due to rash was 7%.

Interim Analysis of C208 Study – Evaluation of Twice-Daily Dosing in HCV Genotype 1 Patients

Interim results from an ongoing, Phase 2, open-label, randomized study examining a twice-daily (q12h) telaprevir dosing regimen versus a three-times-daily (q8h) regimen in combination with RBV and peg-IFN-alfa-2a (PEGASYS®) or peg-IFN-alfa-2b (PEGINTRON™) in treatment-naïve genotype 1 HCV patients suggest the potential for twice-daily dosing of telaprevir. A summary of this interim analysis is shown below:

C208 Treatment Assignment

Interim Undetectable HCV RNA
(<10 IU/mL) at Week 4 and 12
Week 4 Week 12

q8h alfa-2a (n=40)(1)
80% (32 of 40) 93% (37 of 40)

q8h alfa-2b (n=42)(1)
69% (29 of 42) 93% (39 of 42)

q12h alfa-2a (n=40)(2)
83% (33 of 40) 83% (33 of 40)

q12h alfa-2b (n=39)(2)
67% (26 of 39) 85% (33 of 39)


[1] Patients receiving telaprevir (750mg)/peg-IFN/RBV (800-1200mg/d).

[2] Patients receiving telaprevir (1125mg)/peg-IFN/RBV (1000-1200mg/d).

In this analysis, 4 patients (10%) in the q8h alfa-2a and 2 patients (5%) in the q8h alfa-2b arms discontinued due to adverse events and 1 patient (3%) and 3 patients (7%), respectively, experienced virologic breakthrough. In the q12h alfa-2a and q12h alfa-2b arms, 4 patients (10%) and 3 patients (8%), respectively, discontinued due to adverse events, and 2 patients (5%) and 3 patients (8%), respectively, experienced virologic breakthrough.

Phase 3 Registration Programs – ADVANCE and REALIZE

Vertex and Tibotec have completed enrollment in the global 3-arm pivotal Phase 3 ADVANCE trial that is focused on 24-week telaprevir-based response guided regimens in genotype 1 treatment-naïve HCV patients. In the ADVANCE study, telaprevir is being dosed for 8 or 12 weeks. Vertex expects to have SVR data from the ADVANCE study in the first half of 2010.

Patient dosing is underway in the Phase 3 REALIZE clinical study of telaprevir in genotype 1 HCV patients who failed to achieve SVR with prior treatment of peg-IFN and RBV. This study is focused on 48-week telaprevir-based regimens, which include dosing of telaprevir for 12 weeks. REALIZE is expected to complete enrollment of approximately 650 patients in the United States and Europe in the first quarter of 2009.‹

[DewDiligence]

Yesterday’s Bocprevir PR for archival
purposes—the prior PR’s from which to
determine what’s new are as follows:

#msg-31189981 SPRINT-1 interim data
#msg-31190433 Comparison to PROVE-1/2
#msg-31442799 Why 28-wk arms are only ones that matter

http://biz.yahoo.com/prnews/081101/ny43408.html

›Boceprevir Phase II Study Showed High Rate of Sustained Response With 28- and 48-Week Regimens in Genotype 1 Treatment-Naive Hepatitis C Patients

Saturday November 1, 11:00 am ET

Interim results of HCV SPRINT-1 study presented at AASLD annual meeting

Pivotal Phase III studies ongoing in treatment naive patients and those who failed prior treatment

SAN FRANCISCO, Nov. 1 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP ) today reported that a planned interim analysis of a Phase II study showed that boceprevir, its investigational oral hepatitis C protease inhibitor, in combination with peginterferon and ribavirin markedly increased sustained virologic response (SVR) rates with 28 weeks of therapy and nearly doubled SVR with 48 weeks of therapy compared to current standard of care, peginterferon and ribavirin (control group) for 48 weeks. These results from the HCV SPRINT-1 study in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 59th American Association for the Study of Liver Diseases (AASLD) Annual Meeting.(1)

In a 48-week boceprevir regimen, the SVR rate was 74 percent at 12 weeks after the end of treatment (SVR 12) in patients who received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) prior to the addition of boceprevir (800 mg TID) (P/R lead-in). In a 28-week boceprevir regimen, the SVR rate was 56 percent at 24 weeks after the end of treatment (SVR 24) in patients who received the P/R lead-in. These results compared to a 38 percent SVR rate (SVR 12) for patients in the control group receiving 48-weeks of PEGINTRON and REBETOL alone (ITT).(2-4)

Importantly, predictability of attaining SVR 12 or 24 based on rapid virologic response (RVR) was greater for boceprevir patients in the lead-in arms compared to the no lead-in arms. In addition, fewer patients in the lead-in arms discontinued treatment due to viral breakthrough. RVR is defined as undetectable virus (HCV-RNA) in plasma on or before week 4 of boceprevir treatment.

"The high response rates seen with boceprevir in this study are very exciting, especially given that genotype 1 is the most common and hardest to treat form of hepatitis C," said Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, and lead investigator of the study. "Boceprevir was well tolerated by patients in this study, and the use of the 4-week lead-in prior to the addition of boceprevir appears to reduce the incidence of viral breakthrough regardless of treatment duration and may improve SVR over a 48-week treatment period."

The rationale for this novel lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, so patients have the protease inhibitor added at a time when the backbone drug levels have been optimized. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral, potentially reducing the likelihood for the development of resistance.

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. No increase in skin adverse events (rash or pruritus) was observed in the boceprevir arms beyond what was seen in the PEGINTRON and REBETOL control arm.

Treatment discontinuations due to adverse events were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations for boceprevir patients due to viral breakthrough were fewer in the 28- and 48-week lead-in arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and 11 percent, respectively).

About the HCV SPRINT-1 Study

In this Phase II study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) was evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment), boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks, and, in Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily based on patient weight) for 48 weeks, compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). The primary endpoint of the study is SVR after 24 weeks of follow up (SVR 24). This is an ongoing study and SVR 24 rates are not yet available for patients in the 48-week boceprevir arms or the 48-week control arm of the study. In addition, SVR rates are not yet available and consequently results are not being reported for the boceprevir arm with low-dose REBETOL (n=59) compared to contemporaneous control (n=16) as described above.

Sustained Virologic Response (ITT)*

Treatment Arm All patients
No P/R Lead-in 28 Weeks 55% (59/107)
P/R Lead-in 28 Weeks 56% (58/103)
No P/R Lead-in 48 Weeks 66% (68/103)
P/R Lead-in 48 Weeks 74% (76/103)
P/R Control 48 Weeks 38% (39/104)


P/R Lead-in = PEGINTRON and REBETOL for 4 weeks prior to the addition of boceprevir
P/R Control = PEGINTRON and REBETOL alone for 48 weeks
* SVR 12 for 48 week arms; SVR 24 for 28 week arms(2-4)

In the study, predictability of attaining SVR (12 or 24) based on rapid virologic response (RVR) following 28 or 48 weeks of the boceprevir regimen was greater for patients in the lead-in arms (82 and 92 percent respectively) compared to the no lead-in arms (74 and 82 percent, respectively).

The HCV SPRINT-1 study was conducted at sites across the United States, Canada and Europe. Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represent 16 percent of the patients enrolled and 7 percent of patients in the study are cirrhotic.

Update on Boceprevir Phase III Studies

Schering-Plough is conducting two large ongoing pivotal Phase III studies of boceprevir in patients chronically infected with HCV genotype 1. One study is in treatment-naive patients and the other in patients who failed prior treatment (relapsers and nonresponders). The two randomized, double-blind, placebo-controlled studies evaluate the efficacy of boceprevir in combination with PEGINTRON and REBETOL compared to standard of care with PEGINTRON and REBETOL alone.

The study in treatment-naive patients is known as HCV SPRINT-2 and the study in patients who failed prior treatment is known as HCV RESPOND-2. The two studies are expected to enroll a total of more than 1,400 patients at U.S. and international sites.

For more information about these ongoing Phase III studies, please visit www.clinicaltrials.gov, search term boceprevir.‹

[DewDiligence]

What, exactly, is new in messages #68111-68112?

Don’t be shy! (I don’t want to do all of the work :- ))