Valeant Announces Results of Phase 3 VISER 1 Trial of Viramidine versus Ribaviri

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Valeant Announces Results of Phase 3 VISER 1 Trial of Viramidine

versus Ribavirin

By Baker, PhD

Valeant Pharmaceuticals reported preliminary summary results this

week of the VISER 1 Phase 3 trial of Viramidine (taribavirin) versus

ribavirin when both drugs are administered in combination with

peginterferon alfa-2b (PegIntron) in treatment-naïve patients with

chronic hepatitis C.

The VISER 1 trial enrolled 970 patients and included two primary

endpoints (1) Safety: Viramidine superiority to ribavirin in the

incidence of anemia; and (2) Efficacy: Viramidine non-inferiority to

ribavirin in effectiveness (sustained viral response [sVR]).

The summary report does not examine data from the trial on genotype,

HCV viral load, ethnicity, age, HCV disease progression, or other

parameters. These important data will be presented later this year

and in 2007 at scientific meetings such as EASL 2006, DDW 2006 and

AASLD 2006. The summary report summarized here concerns almost

exclusively the 2 primary endpoints of safety and efficacy.

According to the company's announcement, the VISER 1 summary results

confirmed the superior safety profile of Viramidine. Anemia rates

(hemoglobin <10g/dL) were statistically significantly lower in

patients treated with Viramidine than in those treated with ribavirin

(5 percent versus 24 percent; p<0.0001).

However, Viramidine did not meet the non-inferiority to ribavirin

efficacy endpoint on an intent-to-treat (ITT) basis that included 637

patients in the analysis.

Did Lack of Weight-based Dosing for Viramidine Skew the Efficacy Data?

Valeant argues that if the trial had employed weight-based dosing for

Viramidine (as was done for ribavirin), Viramidine would have met the

non-inferiority to ribavirin efficacy endpoint. They also question

the accuracy of the 78% SVR for ribavirin reported in the " rest of

world " region: " The SVR rates were adversely impacted by the effect

of lower dosing on a mg/kg basis in the Viramidine arm and by

statistically inconsistent results seen in the " rest of world " (ROW)

region that comprised 148 participants in the ribavirin arm,

according to the company.

The overall ITT SVR rate for Viramidine was 38 percent versus 52

percent for ribavirin. However, on a per protocol (PP) basis, the SVR

rates for Viramidine in North America (NA) and Europe (EU) combined

were 51 percent versus 56 percent for Viramidine and ribavirin,

respectively. In these same regions, the SVR rates for patients

weighing less than or equal to 75 kilograms were 62 percent for

Viramidine versus 60 percent for ribavirin. In both of these

analyses, says Valeant, the Viramidine SVR rates met the non-

inferiority criteria.

C. Tyson, president and CEO of Valeant, said, " The first

Viramidine Phase 3 study continues to demonstrate that Viramidine

results in a significant reduction in anemia compared to ribavirin. I

am also excited that the weight-based analysis indicates higher

Viramidine dosing is associated with higher efficacy without losing

the superior safety profile with respect to anemia. We continue to

work toward commercial launch of Viramidine before the end of 2007. "

Per protocol analyses in the following table highlights the impact of

body weight and the ROW anomaly on SVR rates.

VISER 1:

Efficacy Percent of Patients with Undetectable HCV RNA*

(Per Protocol Analysis**)

Overall (N=637)

Region Viramidine Ribavirin Adjusted difference of proportion and

95% confidence intervals

Overall (N=637) 52% 62% 0.074

-0.002, 0.151

ROW (N=148)

(Rest of world)

55% 78% 0.209

0.052, 0.365

NA & EU (N=489) 51%*** 56% 0.029

-0.060, 0.118

NA & EU <= 75 kg (N=218) 62%*** 60% -0.049

-0.177, 0.079

NA & EU > 75 kg (N=271) 42% 53% 0.090

-0.034, 0.213

* NGI SuperQuant Assay, sensitivity to 39 IU/mL (100 copies/mL)

** Defined as patients receiving 90% of peginterferon doses, 90% of

ribavirin or Viramidine doses and completing the intended treatment

duration. Excludes protocol violations. The per protocol analyses

were defined before the study was unblinded in the Statistical

Analysis Plan in agreement with the FDA.

*** Met non-inferiority criteria as compared to ribavirin.

Kim D. Lamon, M.D., Ph.D., Valeant's president, research and

development, and chief scientific officer, noted, " The VISER 1 trial

provided sufficient data to show that Viramidine demonstrates

meaningful clinical efficacy and superior safety and allows patients

to complete optimal therapy by minimizing the chance of experiencing

dose reductions or discontinuations as the result of the toxicity of

anemia.

" Other analyses of the trial data clearly demonstrate that increasing

mg/kg concentrations of Viramidine improve the response rate without

a proportionate increase in the incidence of anemia, " according to

Dr. Lamon.

" In addition, said Dr. Lamon, " the inconsistencies coming from ROW

sites, which represented approximately 20 percent of the entire

population, are an anomaly that confounds the overall results.

Reviews of all investigative sites in these countries are underway.

Other adverse events did not appreciably increase with higher doses

of Viramidine. "

Additional planned analyses of the data based on weight (mg/kg)

indicated that SVR was improved with increased mg/kg concentrations

while preserving the safety benefit as summarized below:

VISER 1:

Viramidine* Weight-Based Analysis Percent of Patients with

Undetectable HCV RNA (Per Protocol Analysis)

Viramidine Dose N SVR Anemia (Hgb <10 g/dL)

& #8804;18 mg/kg

323 47% 4.3%

19-22 mg/kg 82 66% 2.4%

& #8805;23 mg/kg 16 81% 12.5%

*Fixed dose of Viramidine averaged approximately 15 mg/kg, based on

mean weight for the study population.

Adverse events other than anemia were similar between treatment

groups. The most common other adverse events associated with

combination therapy included fatigue, headache, insomnia, depression,

and myalgia.

Slides of Summary Data from VISER 1 Phase 3 Trial of Viramidine vs

Ribavirin

VISER 1 Trial Design

The VISER1 trial (VISER stands for VIramidine's Safety and Efficacy

vs. Ribavirin) compared a 600 mg BID fixed dose of Viramidine to a

weight-based 1,000/1,200 mg daily dose of ribavirin, both in

combination with peginterferon alfa-2b.

The study, conducted in the United States, Canada, Europe, Israel,

New Zealand and Australia, enrolled 970 treatment-naïve subjects with

chronic HCV. Treatment duration was based on genotype, with genotypes

2 and 3 receiving 24 weeks of treatment and genotype non 2, 3

receiving 48 weeks of treatment, each with a post-treatment follow-up

period of 24 weeks. The study was stratified for genotype, weight,

and viral load.

Additional information regarding the Phase 3 trial was furnished by

the company to the Securities and Exchange Commission on Form 8-K and

is also available on the company's Web site at www.valeant.com

Viramidine is an investigational compound that has not been found by

the Food and Drug Administration (FDA) or any other regulatory agency

to be safe or effective in the diagnosis, mitigation, treatment or

cure of any disease or illness. It may not be sold or promoted in the

United States unless and until FDA has approved a New Drug

Application. Similar restrictions apply in other countries.

Commentary

In a March 22 conference call with HCV community members and

treatment advocates, Valeant spokespersons said the company will be

meeting soon with the US Food and Drug Administration (FDA) and

European Union drug regulators to discuss the complete data set from

the VISER 1 Phase 3 trial.

VISER 2, a second Phase 3 Viramidine trial, is currently underway

with preliminary data expected from its conclusion and follow-up in

late June 2006. VISER 2 is a multi-center, randomized, double-blind,

clinical research trial that is evaluating in treatment-naïve adult

patients with chronic hepatitis C the efficacy and safety of

Viramidine 600 mg twice a day (BID) compared to ribavirin (Copegus)

1000mg or 1200mg/day, when administered in combination with pegylated

interferon alfa-2a (Pegasys).

NDA for Viramidine?

Valeant hopes to convince the FDA to accept its NDA for Viramidine on

the basis of its proven safety superiority to ribavirin. It will be

up to FDA (and European regulators) to decide whether they will

approve Viramidine for prescription status in the US and Europe

without data from a study conclusively demonstrating that when

utilized with weight-based dosing, the drug is non-inferior to

ribavirin.

Valeant could ask the agency to approve the drug with a commitment

from the company to conduct a Phase 4 post-marketing study that

evaluates its efficacy when used with weight-based dosing.

Valeant characterized a possible " path to market " with the following

timelines and milestones:

VISER 1 Presentation at EASL 2006 or DDW 2006 (1st quarter 2006)

VISER 2 Follow-up Completed (end of June 2006)

VISER 2 Analyses Completed (2nd quarter 2006)

VISER 2 Presentation at AASLD 2006 and CROI 2007 (4th quarter 2006;

1st quarter 2007)