BOSTON, Oct. 27 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. today announced new data from three clinical studies of telbivudine for the treatment of chronic hepatitis B (CHB). Data from the second year of the GLOBE study suggest that viral clearance within the first six months of therapy is associated with better outcomes at one and two years of treatment. Additional results from phase III and phase IIIb studies show that CHB patients treated with telbivudine achieved greater viral clearance at 24 weeks of treatment than patients treated with either lamivudine or adefovir. Additionally, CHB patients who switched to telbivudine achieved greater viral suppression than those who continued on lamivudine or adefovir. These study results will be presented at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, which began today.
Two-year results from the GLOBE study, a phase III clinical trial with 1,367 patients comparing telbivudine with lamivudine, showed that in HBeAg-negative patients, undetectable virus levels (PCR-negativity) were achieved by 82 percent of telbivudine-treated patients and 57 percent of lamivudine-treated patients. In HBeAg-positive patients, 56 percent of telbivudine-treated patients and 39 percent of lamivudine-treated patients achieved viral clearance. These data are based on a comprehensive intent-to-treat analysis including all patients initially enrolled in the trial.
Analysis of two year outcomes in patients who achieved PCR negativity by 24 weeks demonstrate that these patients are more likely to achieve greater HBeAg seroconversion rates, greater undetectable virus level rates, greater liver enzyme (ALT) normalization rates, and lower rates of resistance to therapy. In HBeAg-negative patients, 80 percent of telbivudine-treated patients and 71 percent of lamivudine-treated patients achieved PCR-negativity in the first 24 weeks of treatment. In HBeAg-positive patients, PCR-negativity was achieved by 45 percent of telbivudine-treated patients and 32 percent of lamivudine-treated patients.
“In a chronic disease that often requires long-term treatment, it is important to know how patients may respond over time,” said Adrian M. Di Bisceglie, M.D., Professor of Medicine, Chief of Hepatology, Division of Gastroenterology and Hepatology, Saint Louis University and Co-Director, Saint Louis University Liver Center, USA. “As a robust two-year analysis of a hepatitis B treatment, the GLOBE results provide further evidence that the 24-week antiviral response is associated with improved clinical outcomes at two years.”
The most common adverse events (>5%) in the one-year results of the GLOBE study were upper respiratory tract infection (14%), fatigue and malaise (12%), abdominal pain (12%), nasopharyngitis (11%), headache (11%), blood CPK increased (9%), cough (7%), nausea and vomiting (7%), influenza and influenza-like symptoms (7%), post-procedural pain (7%), diarrhea and loose stools (7%) and pharyngolaryngeal pain (5%).
Results from a phase IIIb study comparing telbivudine with adefovir showed that telbivudine provided greater antiviral activity over adefovir, the leading hepatitis B treatment in the U.S., after 52 weeks of treatment. Patients who switched from adefovir treatment to telbivudine treatment at 24 weeks achieved a mean HBV DNA reduction of -6.44 log(10) copies/mL at one year and patients who remained on adefovir therapy for the full year achieved a mean HBV DNA reduction of -5.72 log(10) copies/mL. In a second phase IIIb study in lamivudine-experienced patients comparing telbivudine with lamivudine, those patients who switched to telbivudine from lamivudine achieved greater viral suppression than those who remained on lamivudine (median HBV DNA reduction of -1.66 log(10) copies/mL vs. -0.95 log(10) copies/mL, respectively).
Approximately 350 million people worldwide are living with CHB(1), a virus that affects the liver and is estimated to be 50 to 100 times more infectious than human immunodeficiency virus (HIV)(1). HBV can cause chronic lifelong infection(2).
Telbivudine, which will be called TYZEKA(TM) in the United States and Sebivo(R) in all other countries, has been approved in the U.S., Switzerland, Brazil, Peru and India. Applications for approval were filed with the European Medicines Agency (EMEA) and the Chinese health authority in the first quarter of 2006. [0]
Additional Findings From The GLOBE Study
The primary efficacy endpoint of the GLOBE study at one year was therapeutic response, a composite endpoint coupling viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable hepatitis B e-antigen (HBeAg). At one year, therapeutic response was 75 percent in HBeAg-positive patients treated with telbivudine and 67 percent in those patients treated with lamivudine, while the response was 75 percent and 77 percent, respectively, for HBeAg-negative patients. At two years, in HBeAg-positive patients, therapeutic response was 64 percent among patients treated with telbivudine and 48 percent for those patients treated with lamivudine, while the response was 78 percent and 66 percent, respectively, for HBeAg-negative patients. Telbivudine achieved mean HBV DNA reduction at two years of -5.7 log(10) in HBeAg-positive patients and -5.0 log(10) in HBeAg-negative patients. Lamivudine-treated patients achieved mean HBV DNA reductions of -4.4 log(10) in HBeAg-positive patients and -4.2 log(10) in HBeAg-negative patients.
At two years, 35 percent of patients taking telbivudine lost HBe antigen during therapy, an important clinical endpoint for HBeAg-positive patients and 29 percent of lamivudine patients achieved this endpoint.
In the guideline treatment eligible HBeAg-positive patient population (baseline ALT greater than twice the upper limit of normal), 41 percent of telbivudine-treated patients and 33 percent of lamivudine-treated patients achieved HBeAg loss. Thirty-six percent of telbivudine-treated patients and 28 percent of lamivudine-treated patients in this population achieved HBeAg seroconversion.
Achieving PCR negativity early in therapy decreased the incidence of viral resistance. For telbivudine-treated patients who achieved PCR negativity at week 24, the per-protocol rates of resistance at two years were 4 percent in HBeAg-positive patients and 2 percent HBeAg-negative patients. Per GLOBE study protocol, resistance was defined as HBV DNA return to >5 log, or to within 1 log of baseline. At 2 years, in HBeAg-positive patients, 17.8 percent of telbivudine patients and 30.1 percent of lamivudine patients exhibited viral resistance per protocol. In the HBeAg-negative patient group, 7.3 percent of telbivudine patients and 16.6 percent of lamivudine patients exhibited viral resistance per protocol. Analysis of viral resistance defined as rebound of HBV DNA after initial suppression to 1 log increase above nadir was also performed and was found in 21.6 percent of telbivudine patients and 35.0 percent of lamivudine patients in the HBeAg-positive group and in 8.6 percent and 21.9 percent, respectively, in the HBeAg-negative group.
Disease exacerbation (ALT flares) occurred in 2.8 percent of telbivudine patients and 8.4 percent of lamivudine. Using AASLD criteria, ALT flares in this case are defined as ALT>10x ULN and >2.0 x baseline. Grade 3/4 creatine kinase (CK) elevations were experienced in 13 percent of telbivudine patients and 4 percent of lamivudine patients.
Additional Findings From The Switch Studies
A one-year open label head-to-head trial against adefovir was designed to evaluate whether HBeAg-positive CHB patients previously treated with adefovir would benefit from switching to telbivudine compared to continued adefovir treatment. Greater reductions in viral load were seen both in patients who received telbivudine for the 52-week duration of the trial (-6.55 log(10) copies/mL) and in those who were switched to telbivudine after 24 weeks of adefovir treatment (-6.44 log(10) copies/mL) compared with those patients treated with adefovir for the duration of the trial (-5.72log(10) copies/mL).
The adefovir vs. telbivudine study (018 study) enrolled 135 adults with HBeAg-positive compensated chronic hepatitis B. Patients were initially randomized (2:1) to adefovir 10 mg/d or telbivudine 600 mg/d for 24 weeks, with a secondary randomization (1:1) at baseline of adefovir recipients to either continue adefovir or switch to telbivudine at week 24.
In a study of patients previously treated with lamivudine, patients who switched to telbivudine achieved median HBV DNA reductions at 24 weeks of -1.66 log(10) copies/mL compared to -0.95 log(10) copies/mL for patients who continued lamivudine treatment. The lamivudine switch study enrolled patients previously treated with lamivudine for 3-12 months. Patients were randomized to either continue lamivudine (100mg/day) or switch to telbivudine (600mg/day) for one year.
Important Information About TYZEKA (telbivudine)
Indications and Usage
TYZEKA (TM) (telbivudine) is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
This indication is based on virologic, serologic, biochemical and histologic responses after one year of treatment in nucleoside-treatment-naive adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease.
Important Safety Information * Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. * Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including TYZEKA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted. * Cases of myopathy have been reported with TYZEKA use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Physicians considering concomitant treatment with these or other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor and advise patients to report any signs or symptoms of unexplained muscle pain, tenderness or weakness, particularly during periods of upward dosage titration. TYZEKA therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is diagnosed. * Because TYZEKA is eliminated primarily by renal excretion, co-administration of TYZEKA with drugs that affect renal function may alter plasma concentrations of TYZEKA and/or the co-administered drug. Dose interval adjustment is recommended in patients with creatinine clearance < 50mL/min. * The safety and efficacy of TYZEKA in liver transplant recipients are unknown. If TYZEKA treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with TYZEKA. * Patients should be advised that treatment with TYZEKA has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. * Safety and effectiveness of TYZEKA in pediatric patients under the age of 16 years have not been established * Selected treatment-emergent clinical adverse events (Grade 2-4) of moderate to severe intensity reported in the GLOBE study with TYZEKA were: muscle-related symptoms 2%; fatigue/malaise 1%; headache 1%; pyrexia 1%; abdominal pain <1%; arthralgia <1%; cough <1%; diarrhea <1%; gastritis <1%. * Creatine kinase (CK) elevations were more frequent among subjects on telbivudine treatment. Grade 3/4 CK elevations occurred in 9% of telbivudine-treated patients and 3% of lamivudine-treated patients. * The optimal treatment duration with TYZEKA has not been established. The relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown. Idenix/Novartis Collaboration
Idenix is co-promoting its hepatitis B product, TYZEKA, and developing its hepatitis B and hepatitis C clinical product candidates, (valtorcitabine and valopicitabine, respectively), in collaboration with Novartis Pharma AG under a development and commercialization agreement established in May 2003. Under this agreement, Novartis and Idenix will co-promote TYZEKA, and if successfully developed, valtorcitabine and valopicitabine, in the United States, France, Germany, Italy, Spain and the United Kingdom. Novartis has the exclusive right to commercialize licensed approved products in the rest of the world.
Forward-looking Statements
This press release contains “forward-looking statements” within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements can be identified by the use of forward-looking terminology such as “can cause,” “can lead to,” “look forward to,” “will,” “may be” or similar expressions or by express or implied discussions regarding potential approvals of telbivudine, the potential future development of other products, or potential future revenues from telbivudine or any other products. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantees that telbivudine or any other products will be approved for sale in any markets or that, these product will achieve any particular levels of revenue. In particular, management’s expectations could be affected by unexpected regulatory actions or delays, or government regulation generally; unexpected clinical trial results, including additional analysis of existing clinical data and new clinical data; the ability to advance valopicitabine into phase III clinical trials, the company’s ability to obtain additional funding required to conduct its research, development and commercialization activities; the ability of the company to attract and retain qualified personnel; competition in general; government, industry, and general public pricing pressures; and the company’s ability to obtain, maintain and enforce patent and other intellectual property protection for telbivudine, valopicitabine, its other product candidates and its discoveries. These and other risks which may impact management’s expectations regarding telbivudine and Idenix’s other product candidates are described in greater detail under the caption “Risk Factors” in the company’s annual report on Form 10-K for the year ended December 31, 2005 as filed with the Securities and Exchange Commission and other filings that the company makes with the Securities and Exchange Commission.
All forward-looking statements reflect the company’s expectations only as of the date of this release and should not be relied upon as reflecting the company’s views, expectations or beliefs at any date subsequent to the date of this release. Idenix anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
References
1. Lavanchy D. J Viral Hepatology. 2004 Mar 11 (2): 97-107
2. World Health Organization. Hepatitis B. Available at: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html .
Idenix Pharmaceuticals’ Contacts:
Media: Teri Dahlman (617) 995-9905
Investors: Amy Sullivan (617) 995-9838
Idenix Pharmaceuticals, Inc.
CONTACT: Media, Teri Dahlman, +1-617-995-9905, or Investors, Amy Sullivan,+1-617-995-9838, both of Idenix Pharmaceuticals, Inc.
Web site: http://www.idenix.com/
