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Digestive Disease Weekly (DDW)
Special Report – VX 950

Vertex Announces New Clinical Trials

Alan Franciscus
Editor-in-Chief, HCV Advocate

The report on VX-950 was presented at this year’s Digestive Disease Week Conference.  There was new information about a variety of experimental drugs presented this year, but the presentation that garnered the most attention was “28 Days of the Hepatitis C Protease Inhibitor VX-950, in Combination with Peg-Interferon-Alfa-2a and Ribavirin, is Well-Tolerated and Demonstrates Robust Antiviral Effects (abstract 686f).

There has been a high level of excitement about VX-950 since results from a trial on VX-950 combined with peginterferon alfa-2a (Pegasys) were released last year.  The results found that VX-950 alone and in combination with Pegasys was well-tolerated and produced significant HCV RNA (viral load) reductions in only 14 days.

Twelve patients were enrolled in this study to assess the safety and the antiviral response of VX-950 when given in the combination with Pegasys plus ribavirin.  All patients in the study were HCV treatment naïve (never been treated) genotype 1 patients.

Patient Characteristics
   
Gender
Males 6 Patients
Females 6 Patients
   
Race
Caucasian 1 Patient
Hispanic 10 Patients
Other Race 1 Patient
   
Median Weight 78.7 kg
Median Age 43.7 yo
   
Histology (ISHAK)
No/Mild histology 6 Patients
Portal fibrosis 4 Patients
Bridging fibrosis 3 Patients

Methods
All trial participants received 750 mg (oral tablet) every 8 hours of VX-950, 180 µg of Pegasys weekly, and ribavirin 1000 or 1200 mg daily.   Patients were treated with VX-950 for 28 days.  At the end of the VX-950 treatment period, all 12 patients continued to receive Pegasys and ribavirin for the standard duration of treatment (48 weeks). 

It was found that VX-950 in combination with Pegasys and ribavirin was well-tolerated.  There were no serious adverse events (side effects) and no patients discontinued treatment.  The most common side effects reported were fatigue, headache, nausea, anemia, depression, itching and rash.  One patient had a headache that was graded as severe.  It was noted that the side effects reported are what you would expect from interferon plus ribavirin therapy.

Results
The results showed a highly significant reduction in HCV RNA levels:

  • At the end of week 2, plasma HCV RNA was below the limit of quantitation (30 IU/mL) in 11 of the 12 patients; and undetectable (less than 10 IU/mL) in three of 12 patients.

  • At the end of week 3, plasma HCV RNA was below the limit of quantitation (30 IU/mL) in all patients (12 of the 12); and undetectable (less than 10 IU/mL) in nine of 12 patients.

  • At the end of VX-950 dosing (end of week 4; day 28), plasma HCV RNA was undetectable (less than 10 IU/mL) in all 12 patients.

HCV RNA Day 8 Day 15 Day 22 Day 28
> 30 IU/mL 6 1 0 0
< 30 IU/mL 6 11 12 12
< 10 IU/mL 2 3 9 12

Importantly, no patients showed evidence of viral breakthrough while receiving VX-950 treatment.

Follow-up:

  • At week 12 of follow-up 11 patients had HCV RNA below the limit of detection (10 IU/mL).  The patient with detectable HCV RNA levels at week 12 of follow-up did not have undetectable HCV RNA (less than 10 IU/mL) until the 4th week of VX-950 dosing. 

  • HCV RNA (viral load) was detectable (less than 30 IU/mL) in one patient two weeks after stopping VX-950 dosing, it was undetectable for the next 8 weeks, becoming detectable again after 12 weeks of continued pegylated interferon plus ribavirin dosing.

  • At week 16 of follow-up, HCV RNA in this patient was 490 IU/mL.  Blood samples from this patient are being collected for viral sequencing and this patient continues to receive pegylated interferon plus ribavirin. 

The lead investigator, Dr. Lawitz, commented that "28 days of therapy with the combination of VX-950, Pegasys and ribavirin resulted in unprecedented antiviral activity, with all 12 genotype 1 patients reaching viral levels below the limits of detection at the end of dosing at 28 days and that the combination of pegylated interferon plus ribavirin will hopefully preserve the response in these patients." 

The authors noted that the combination of VX-950, Pegasys and ribavirin was well tolerated for 28 days in patients with genotype 1.  The data showed that the combination therapy produced rapid and significant viral reductions with all patients achieving undetectable HCV RNA (viral load) within the 28 day dosing period.  “I am optimistic about these early results for the future of HCV treatment,” commented Dr. Lawitz, “and we hope that there will be a paradigm shift with higher sustained response rates with shorter durations of therapy for genotype 1 Hepatitis C in the future.”

 Sources:
Abstract 686f - 28 Days of the Hepatitis C Protease Inhibitor VX-950, in Combination with Peg-Interferon-Alfa-2a and Ribavirin, is Well-Tolerated and Demonstrates Robust Antiviral Effects

E. J. Lawitz1; M. Rodriguez-Torres2; A. Muir3; J. Keane4; T. Kieffer4; L. McNair4; J. G. McHutchison3

1. Alamo Medical Research, SanAntonio, TX, USA.
2. Fundacion de Investigation de Diego , Santurce, Puerto Rico.
3. Duke Clinical Research Institute & Division of Gastroenterology, Duke University, Durham, NC, USA.
4. Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA.

Vertex company press release:  5/21/06
Interview with E. Lawitz:  5/25/06
 

Vertex Announces Two New Major Phase II Clinical Trials

In a related story, Vertex announced the initiation of two new major Phase II clinical trials of VX-950 named--Investigation of HCV Protease Inhibition for Viral Eradication (PROVE). 

U.S. - PROVE 1
PROVE 1 is a U.S. study which will begin the first dosing in patients in June 2006.  The primary objective of this study is to assess the proportion of patients in each of four arms who achieve a sustained virological response (defined as undetectable—less than 10 IU/mL as measured by Taqman assay) with shorter duration of treatment.  260 HCV positive patients will be randomized into one of four arms or groups (table 1).   Information on this clinical trial will be posted to www.clinicaltrials.gov when available.

Europe – PROVE 2
A similar study is being initiated in Europe in more than 20 centers and will randomize 320 HCV positive patients into four treatment arms (table 1).   

Table 1.

Phase II Studies for VX-950
Treatment Regimen Patients in PROVE 1 Patients in PROVE 2 Total
12-week regimens of VX-950 in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) 20 80 100
12-week regimens of VX-950 in combination with only pegylated interferon (peg-IFN) 0 80 80
12-week regimens of VX-950 in combination with pegylated interferon (peg-IFN) and ribavirin (RBV), followed by 12 weeks of therapy with peg-IFN and RBV 80 80 160
12-week regimens of VX-950 in combination with pegylated interferon (peg-IFN) and ribavirin (RBV), followed by 36 weeks of therapy with peg-IFN and RBV 80 0 80
Standard of Care HCV Treatment 80 80 160
Total 260 320 580

*Standard of Care HCV Treatment is defined as peg-IFN and ribavirin for 48 weeks

Vertex also plans to study VX-950 in patients who failed prior standard of care therapy as well as a multi-dose, drug-drug interaction study of VX-950 and low dose ritonavir.  



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