Biotech Values

[DewDiligence]

VRTX Reports Interim Telaprevir Data from Open-Label Extension Study of Patients Who Failed in the Control Arm of PROVE-1 or PROVE-2

[The abstract for this presentation was released on March 31 and caused a 30% pop in VRTX’s share price (#msg-28067384). Now we know the details: these data from the so-called ‘107’ study could be a harbinger of good results in VRTX’s PROVE-3 study (#msg-16715663), the phase-2 randomized trial in progress in treatment-experienced HCV that could conceivably be an avenue for VRTX to seek FDA approval of Telaprevir before the phase-3 results in treatment-naïve HCV are completed (#msg-26290780). The interim ‘107’ results reported below include a mixed bag of patients and hence there are a lot of figures to digest in this PR. The main takeaway, however, is that these data are pretty darn good for patients who previously failed an SoC regimen. There is one proviso, however: patients who discontinued PROVE-1 or PROVE-2 for adverse events were not eligible to be enrolled in the ‘107’ study and hence the safety data in the ‘107’ study may be skewed.

Note that the ‘107’ study has been modified to include a variable duration of treatment (24 or 48 weeks) depending on whether a patient showed undetectable virus at both 4 weeks and 12 weeks. This is the same duration-of-treatment algorithm being used in VRTX’s phase-3 ADVANCE trial in the treatment-naïve setting (#msg-27623529). For want of a better term, I call the metric being used “durable RVR” to distinguish it from RVR (which merely requires undetectable virus at week 4) and EVR (which merely requires undetectable virus at week 12).]

http://biz.yahoo.com/bw/080424/20080423006420.html

>>
Thursday April 24, 12:01 am ET

-Interim results to be presented in late-breaker poster presentation at EASL on April 24-

-Significant early on-treatment viral response from patients who previously failed therapy-

MILAN, Italy--(BUSINESS WIRE)--In a late-breaker poster presentation at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), researchers today will present data from an interim analysis of telaprevir (VX-950) in combination with pegylated interferon and ribavirin in genotype 1 chronic hepatitis C patients who failed to achieve SVR with a previous pegylated interferon and ribavirin treatment regimen. The interim results are from the 107 study, an ongoing, open-label study which was designed to provide access to telaprevir in patients who met on-treatment criteria for null or partial response, or relapsed after the completion of 48 weeks of pegylated-interferon (peg-IFN) and ribavirin (RBV), in the control arms of the telaprevir Phase 2b PROVE studies. Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX ) is developing telaprevir in collaboration with Tibotec.

In the interim analysis, patients treated with telaprevir in combination with peg-IFN and RBV demonstrated a high rate of viral response at week 4 (49 of 60 patients achieved HCV RNA <25 IU/mL). This response appears to have been maintained, with no viral breakthrough observed to date in the 36 patients who have completed 4 weeks of treatment and continued out to 8 weeks and in the 16 of those patients who have continued out to 12 weeks of treatment.

“While early, these results are very promising. Patients who have not achieved SVR with prior treatment represent the largest unmet medical need in hepatitis C, as typically only 10% to 15% of those re-treated with current therapies achieve sustained virologic responses. The fact that the most difficult-to-treat patients showed such a profound early response is very encouraging,” said Fred Poordad, M.D., study author of the PROVE 1 and 107 studies, and Chief of Hepatology at the Cedars-Sinai Center for Liver Disease and Transplantation.

The results will be presented in a late-breaker poster titled, “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 today.

Interim Data Analysis Summary – 107 Study

The 107 study results presented at EASL represent an interim analysis for patients who received telaprevir-based therapy. Patients could enroll in the 107 study if they did not achieve SVR in the control arms of the Phase 2b telaprevir studies - PROVE 1, 2 and 3. These patients were followed closely in the PROVE studies and can be well-characterized as null responders, partial responders or relapsers to standard treatment. Null responders are defined as patients who had less than a 1 log10 decrease in HCV RNA at week four or less than a 2 log10 decrease in HCV RNA at week 12. Partial responders are defined as patients who had a greater than 2 log10 decrease in HCV RNA at week 12, but had detectable HCV RNA at week 24. Relapsers are defined as patients who had undetectable HCV RNA at the end of treatment but reverted to detectable levels of HCV RNA after stopping treatment.

The results include data from all enrolled patients in study 107 who received at least one dose of telaprevir-based treatment and who completed the week 4 assessment. At the time of analysis, 72 patients had received at least one dose of study drug and 60 patients had completed week 4. Patients continued treatment at week 4 and 12 if they did not meet the stopping rule criteria, defined as HCV RNA >25 IU/mL (Roche Taqman assay, version 2.0) at either of those time points. Nine patients discontinued all study treatment prior to week 12, including 5 patients who met the week 4 stopping rule, 2 patients who experienced breakthrough (both at week 2), 1 patient who discontinued due to an adverse event, and 1 patient who discontinued due to an adverse event and also met the week 4 stopping rule.

A high proportion of patients, regardless of the patient’s degree of non-response to prior treatment, achieved HCV RNA <25 IU/mL at week four of treatment, and available data as of the interim analysis indicate that in patients who continued past week four, response has been maintained through week 12. Week 4, 8 and 12 on-treatment antiviral responses are summarized in the table below:

Prior Virologic Response in Phase 2 control arm studies1 Interim HCV RNA Results in Patients Reaching Week 4, 8 and 12 Assessments
Week 4
<25 IU/mL Week 4
<10 IU/mL Week 8
<10 IU/mL Week 12
<10 IU/mL
Week 4 null-responder2 18 of 24 8 of 24 10 of 15 8 of 9
Week 12 null-responder2 7 of 10 5 of 10 5 of 5 3 of 3
Partial responder3 18 of 19 15 of 19 9 of 9 1 of 1
Breakthrough4 1 of 1 1 of 1 - 1 of 1
Relapsers5 5 of 6a 4 of 5b 6 of 6 2 of 2
1 Each category represents a separate patient group
2 Null responders defined as non-response week 4 (<1 log10 drop in HCV RNA at week 4) or as non-response week 12 (<2 log10 drop in HCV RNA by week 12)
3 Partial responder defined as 2 log10 drop at week 24; detectable HCV RNA at week 24
4 Breakthrough defined as detectable HCV RNA during treatment after achieving undetectable HCV RNA
5 Relapsers defined as undetectable HCV RNA at end of treatment, but relapsed
a One sample not obtained b Does not include missing sample

A low rate of on-treatment viral breakthrough was observed. Two patients at week 2 experienced viral breakthrough, defined as an increase in HCV RNA on treatment of >1 log10 above HCV RNA nadir or an increase to >100 IU/mL in previously undetectable patients. Viral breakthrough has not been observed in any other patients as of this interim data analysis.

“These data provide the first demonstration of the potential for an HCV protease inhibitor-based regimen to provide significant antiviral activity in patients who have not achieved SVR with current treatments,” said John Alam, M.D., Executive Vice President, Medicines Development, and Chief Medical Officer of Vertex. “While further follow-up data are needed to fully understand telaprevir’s role in the re-treatment of HCV patients, we are very pleased with these early results. This is an important step forward in exploring the opportunity for telaprevir in this important patient population.”

Safety Findings

In the interim analysis, adverse events were similar to those commonly observed with peg-IFN and RBV including fatigue, nausea, rash, headache, gastrointestinal disorders and anemia, and consistent with those previously reported in patients being treated with telaprevir-based therapy in the PROVE studies. Two patients discontinued treatment due to adverse events, including one discontinuation due to pleuritis/costochondritis and one due to generalized rash.

About the Phase 2a 107 Clinical Study

The 107 study is an ongoing, open-label study which was designed to provide access to telaprevir in patients who met on-treatment criteria for null or partial response, or relapsed after the completion of 48 weeks of peg-IFN and RBV in the control arms of the three telaprevir Phase 2b studies. This study provides an opportunity to correlate within individual patients the antiviral response of telaprevir, peg-IFN and RBV to that of their original responses to peg-IFN and RBV.

At the time of enrollment into the 107 study, patients were assigned to receive 12 weeks of telaprevir (750 mg q8 hour) in combination with peg-IFN and RBV at standard doses, followed by 12 weeks of peg-IFN and RBV alone. Patients who discontinued because of adverse events in the PROVE studies were not eligible to enroll in the 107 study.

Based on the results of the PROVE 1 and PROVE 2 clinical studies, which demonstrated a correlation between RVR and SVR in a 24-week telaprevir-based regimen, and the on-treatment antiviral response observed to date in study 107, the study 107 dosing regimen is currently being modified. Partial responders and relapsers, who in the current analysis appear to have a response similar to that of treatment-naïve patients, will receive the response-driven dosing regimen that is being utilized in the Phase 3 ADVANCE study. These patients will be treated for a period of 24 or 48 weeks utilizing a week 4 and week 12 undetectable HCV RNA criteria to determine which patients can stop all treatment at week 24. Partial responders and relapsers who do not achieve undetectable HCV RNA at both weeks 4 and 12 will receive 48 weeks of peg-IFN and RBV at standard doses. [In other words, patients other than prior null responders get a total of 24 weeks of treatment if they show a “durable RVR” and a total of 48 weeks of treatment if they don’t.] In order to maximize potential SVR rates in the substantial number of prior null responders who, to date, have achieved a viral response in study 107, prior null responders will be treated with 12 weeks of telaprevir-based treatment (telaprevir in combination with peg-IFN and RBV) followed by 36 weeks of peg-IFN and RBV alone.
<<