Researchers Report Results for 28-day Phase II Study of VX-950 in Combination wi

[Guest guest]

Researchers Report Results for 28-day Phase II Study of VX-950 in

Combination with Pegylated Interferon and Ribavirin in Hepatitis C

Patients

The actual presentation of the results from this study will be

reported Tuesday at 3:30pm in a Late Breaker oral session. Here is a

Press release from Vertex.

- 12 of 12 (100%) patients HCV RNA undetectable with no evidence of

viral breakthrough at end of 28 days VX-950 dosing -

- 92% (11 of 12) continued to have undetectable HCV RNA through 12

weeks of follow-on therapy -

LOS ANGELES, May 21 /PRNewswire-FirstCall/ -- Data to be presented

this week at the Digestive Disease Week conference show that plasma

HCV RNA was reduced to undetectable levels (less than 10 IU/mL) in

all 12 of 12 (100%) patients with genotype 1 HCV infection treated

with VX-950, an investigational oral hepatitis C virus (HCV) protease

inhibitor being developed by Vertex Pharmaceuticals Incorporated

(Nasdaq: VRTX), in combination with pegylated interferon alfa-2a

(Pegasys®; peg-IFN) and ribavirin (RBV) for 28 days. No viral

breakthrough was observed in any patient during 28 days of VX-950

dosing. All patients completed dosing with no serious adverse

events; those adverse events reported are considered typical of peg-

IFN and RBV combination therapy. All patients enrolled in the 28-day

study subsequently received follow-on treatment

with peg-IFN and RBV. Researchers reported for the first time today

that 11 of these patients (92%) continue to have no detectable virus

in their blood at the end of 12 additional weeks of follow-on peg-

IFN+RBV dosing. The 12th patient was found to have detectable HCV

RNA (less than 30 IU/mL) in the week 12 post-VX-950 follow-up sample,

with continuing evidence of detectable HCV RNA in subsequent samples.

All 12 patients are continuing to receive peg-IFN+RBV.

" With the combination of VX-950, pegylated interferon and ribavirin,

we observed 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, " said Lawitz, M.D., of Alamo Medical

Research in San , the investigator presenting the study

results. " In addition, no serious adverse events were reported, and

those adverse events that were reported are similar to those observed

in previous studies of pegylated interferon and ribavirin. These

results are highly encouraging for the initiation of future VX-950

studies that seek to evaluate the potential for viral eradication

with short duration therapy. "

In addition, researchers reported the results of a viral sequencing

analysis from patients in the 28-day study. These results showed that

despite the detection of treatment-emergent viral variants in two

patients early in the course of VX-950 dosing, combination treatment

with VX-950 resulted in a continuous decline in HCV RNA to

undetectable levels through the initial 28-day dosing period, and HCV

RNA has remained undetectable in these patients through 12 weeks of

follow-on therapy.

Study Design

The 28-day, Phase II clinical study enrolled 12 treatment-naive

patients with genotype 1 HCV. Patients received VX-950 in a tablet

formulation at a dose of 750 mg every eight hours (q8h) for 28 days

in combination with standard doses of pegylated interferon alfa-2a

(Pegasys®; peg-IFN) and ribavirin (Copegus®; RBV). At the end of

28 days, patients completed dosing with VX-950 and per study protocol

were required to continue off-study treatment with peg-IFN and RBV.

This 28-day, Phase II study was not designed to evaluate sustained

viral responses (SVR) in patients receiving VX-950.

Antiviral Results at 28 days

At study entry, the median baseline plasma HCV RNA was 6.5 log10 (3.2

million) IU/mL. At the end of week 1 (day 8 of VX-950 dosing),

plasma HCV RNA was below the limit of quantitation (30 IU/mL; Roche

Taqman® assay) in six of the 12 patients; and undetectable (less

than 10 IU/mL; Roche Taqman® assay) in two of 12 patients.

Preliminary HCV RNA results in patients for weeks 2-4 are as follows:

* 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 12 of the 12 patients; 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.

* No patients showed evidence of viral breakthrough while receiving

VX-950 treatment.

Follow-on Therapy

All 12 patients received follow-on treatment with peg-IFN+RBV therapy

after completing 28 days of combination therapy with VX-950, peg-IFN

and RBV. At week 12 of follow-on therapy, 11 patients had HCV RNA

below the limit of detection (10 IU/mL). The patient with detectable

viral levels at week 12 of follow-on dosing did not have undetectable

HCV RNA (less than 10 IU/mL) until the 4th week of VX-950 dosing.

While

this patient's HCV RNA was again detectable (less than 30 IU/mL) two

weeks after stopping VX-950 dosing, it was undetectable for the next

8 weeks, becoming detectable again after 12 weeks of follow-on peg-

IFN+RBV 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 peg-IFN+RBV

treatment.

Safety

A complete safety review has been conducted. All patients completed

dosing and no serious adverse events were reported. The most common

adverse events observed in the study were flu-like illness, fatigue,

headache, nausea, anemia, depression, itching and rash. All of these

adverse events were mild to moderate in severity, except for one

headache that was graded as severe. All of these adverse events were

considered to be typical of peg-IFN and RBV combination therapy.

On-Treatment Viral Sequencing Analysis

Extensive viral sequencing analyses of the HCV protease catalytic

domain were planned as part of the study, using blood samples

collected at baseline (before VX-950 dosing) and during the 28-day

dosing period. Baseline sequences obtained in all 12 subjects showed

only wild-type RNA. Once dosing was initiated, sequences could be

obtained in all 12 patients at the 24-hour time point, but only in

two patients at the end of the first week of dosing (14 on-treatment

samples total). In all other patients, and at all other time points,

dosing with VX-950 in combination with peg-IFN and RBV suppressed

plasma HCV RNA to levels below the limit of detection of the

sequencing assays.

Using a highly sensitive clonal sequencing approach, 12 of the 14

samples contained 100% wild-type virus. In two samples, one

collected from a patient at 24 hours of dosing and one in another

patient at the end of the first week of dosing, viral variants

consisting predominantly of a V36M amino acid sequence change were

detected, with one sample also showing a low proportion of an A156T

amino acid sequence change. In both these patients with detectable

viral variants, HCV RNA was rapidly suppressed during continued

dosing with VX-950, and both patients became HCV RNA undetectable by

the end of the third week of dosing. HCV RNA remained undetectable in

both of these patients after 12 weeks of follow-on treatment with peg-

IFN and RBV. The results suggest that viral variants may exist at a

low level in patients before VX-950 dosing is initiated, and that

they are uncovered by the rapid reduction of the wild-type virus.

However, in this study these variants were rapidly suppressed to

below detectable levels with VX-950, peg-IFN and RBV combination

therapy.

About Hepatitis C

Hepatitis C is a liver disease caused by the hepatitis C virus, which

is found in the blood of people with the disease. HCV, a serious

public health concern affecting 3.4 million individuals in the United

States, is spread through direct contact with the blood of infected

people. Though many people with hepatitis C may not experience

symptoms, others may have symptoms such as jaundice, abdominal pain,

fatigue and fever. Hepatitis C significantly increases a person's

risk for developing long-term infection, chronic liver disease,

cirrhosis or death. The burden of liver disease associated with HCV

infection is increasing, and current therapies only provide sustained

benefit in about 50% of patients with genotype 1 HCV, the most common

strain of the virus. Specifically targeted antiviral therapies for

HCV in clinical development have the potential to increase the

proportion of patients who can eradicate the virus.

About VX-950

VX-950 is an investigational oral inhibitor of hepatitis C virus

protease, an enzyme essential for viral replication, and is one of

the most advanced investigational agents that specifically targets

HCV. In clinical studies to date of 14 days and 28 days duration,

researchers have observed rapid and dramatic antiviral activity with

VX-950 dosed both as a single agent and in combination. In clinical

studies of VX-950 no patients

have discontinued treatment and no serious adverse events have been

reported. The most common adverse events reported, including

patients who did not receive VX-950, and regardless of possible

relationship to drug, have been headache, frequent urination,

gastrointestinal symptoms, myalgias, skin disorders and chills.

Most of these adverse events have been reported as mild to moderate

in severity.

Vertex researchers were the first to solve the three-dimensional

crystal structure of HCV protease, and have used structural insights

to enable the design of small molecule HCV protease inhibitors,

including VX-950.

About Digestive Disease Week (DDW)

DDW is the largest international gathering of physicians, researchers

and academics in the fields of gastroenterology, hepatology,

endoscopy and gastrointestinal surgery. Jointly sponsored by the

American Association for the Study of Liver Diseases, the American

Gastroenterological Association, the American Society for

Gastrointestinal Endoscopy and the Society for Surgery of the

Alimentary Tract, DDW takes place

May 20-25, 2006, at the Los Angeles Convention Center. The meeting

showcases approximately 5,000 abstracts and hundreds of lectures on

the latest advances in GI research, medicine and technology. For more

information, visit http://www.ddw.org.