Gilead Opens Early Access >Adefovir Dipivoxil Lam -->好阳光转移

liver411

Gilead Opens Early Access Program to Provide Adefovir Dipivoxil Free to Patients with Lamivudine-Resistant Hepatitis B Virus (HBV) Infection



By Ronald Baker, PhD



Gilead Sciences today (March 12, 2002) announced the start in the US of an Early Access Program (EAP) that provides its experimental anti-HBV drug adefovir dipivoxil without cost to people with chronic hepatitis B virus (HBV) infection who are resistant to Epivir-HBV (lamivudine; 3TC).



Early Access Programs (aka "expanded access" programs) are FDA-approved mechanisms operated by the drug sponsor (e.g., Gilead Sciences) that are designed to provide promising experimental drugs without cost to patients with serious or life-threatening medical conditions who have exhausted the benefits of currently available medications. The oral NRTI Epivir-HBV is one of only two FDA-approved agents for the treatment of chronic HCV infection. The other is the injectable Intron A (standard interferon alfa-2b).



"Less than half of patients with chronic HBV are candidates for interferon alfa [Intron A], and resistance to lamivudine [Epivir-HBV] is a key factor in treatment failures. This leaves a large patient population without a viable treatment, many of whom are at serious risk for disease progression," said Robert Perrillo, MD, Ochsner Clinic, New Orleans, LA. "The Adefovir Dipivoxil Chronic Hepatitis B Early Access Program will provide access to a drug that may represent the best hope for these patients."



Studies document that 8-15 percent of HIV positive patients are HbsAg+. Among co-infected patients, lamuvidine-resistant HBV develops in about 24 percent of patients after one year of therapy, in 47 percent after 2 years of therapy, and in 67 percent after four years of therapy.



Preliminary results of an ongoing study of adefovir in patients with lamivudine-resistant HBV presented at the 9th Annual Retrovirus Conference showed promising results. After 24 weeks, the study of 35 HIV/HBV co-infected patients using 10 mg adefovir in addition to continuing Epivir-HBV in combination with two other anti-HIV drugs produced the following conclusions:



• Continued significant antiviral activity against Epivir-HBV-resistant HBV (continued decline of serum HBV DNA);

• Histological improvement;

• HbeAg seroconversion in 12% of co-infected patients;

• No adefovir-related HBV or HIV mutations (through week 48);

• No laboratory or clinical evidence of nephrotoxicity



Results of a 48-week pilot study published in The Lancet (September 1, 2001) also concluded that adefovir is effective in patients co-infected with HBV/HIV who have developed resistance to Epivir-HBV. Mean decreases in serum HBV DNA concentrations from baseline (log 8·64 copies/mL [SE log 0·08]) were -log 3·40 copies/mL [log 0·12] at week 24 (n=31) and -log 4·01 copies/mL [log 0·17] at week 48 (n=29).



Two patients underwent hepatitis B e antigen seroconversion--one at week 32 and one at week 36. No adefovir dipivoxil-associated HBV or HIV resistance mutations were observed during the 48 weeks of treatment.



The EAP program will open initially in the United States, followed by Canada, Australia and countries in Europe as local regulatory approvals for the program are obtained. Based on positive data from two pivotal Phase III studies, Gilead anticipates submitting applications for marketing approval of adefovir dipivoxil 10 mg in the United States and Europe in the first half of 2002.



Expanded Access Program Design

The Early Access Program will make adefovir dipivoxil 10 mg available to patients in the United States 16 years or older with chronic HBV resistant to lamivudine and who are at risk for disease progression. Lamivudine resistance is defined as a positive serum HBV DNA greater than or equal to 106 copies/mL (PCR assay) and ALT greater than or equal to 1.2 times the upper limit of normal within four weeks of screening despite ongoing treatment with lamivudine.



Patients must have received at least 24 cumulative weeks prior treatment with lamivudine and have adequate hematologic and renal function at screening. Those patients co-infected with HIV, HCV or other viral infections will be eligible provided they meet all other entry criteria.



Physicians will be required to evaluate patients at baseline and after one month on therapy, then every two months until drug discontinuation or study termination following the protocol-specified guidelines. Patients enrolled in the US Early Access Program will receive adefovir dipivoxil via their physician until the drug has been licensed for marketing by the US Food and Drug Administration and is commercially available, or until the program is terminated by Gilead Sciences. A similar program was initiated in France in July 2001 and has enrolled 278 patients to date.



"roviding advanced care to patients through improved therapeutics is at the core of the Gilead mission," said John C. Martin, PhD, President and CEO, Gilead Sciences. "Initiating this program is a significant step toward providing early access to adefovir dipivoxil to patients who have become resistant to lamivudine."



Physician Registration

For more information regarding the Adefovir Dipivoxil Chronic Hepatitis B Early Access Program or to request registration materials, physicians may call 1-800-GILEAD-5 or 1-650-574-3000. Parexel is the contract research organization that will manage the program on Gilead's behalf for sites in the United States, Canada, Australia and Europe.



About Adefovir Dipivoxil

Adefovir dipivoxil belongs to a class of drugs called nucleotide analogues which are designed to work by blocking HBV DNA polymerase, an enzyme involved in the replication of HBV in the body. The investigational drug is dosed as one 10 mg tablet taken once daily.



Data from two pivotal Phase III studies were released in 2001. All primary and secondary efficacy endpoints were achieved, and the safety profile of adefovir dipivoxil 10 mg over 48 weeks of dosing was similar to placebo. Study 437 is a Phase III clinical trial evaluating the safety and efficacy of adefovir dipivoxil once daily as monotherapy compared to placebo in 515 hepatitis B "e" antigen-positive patients with chronic HBV infection and compensated liver function. Results from this study were presented at the 52nd Annual meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2001.



Study 438 is an ongoing Phase III clinical trial that enrolled 185 patients with precore mutant HBV, or hepatitis B "e" antigen-negative virus, and compensated liver function. This two-year study is being conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia.



Preliminary results were released in September 2001 and will be presented at the 37th annual meeting of the European Association for the Study of the Liver (EASL) in Madrid in April 2002. Data from these studies will comprise the core of the regulatory filing packages in both the United States and Europe. To further evaluate the long-term safety and resistance profiles of adefovir dipivoxil, some patients are continuing on Studies 437 and 438 for an additional three years of treatment.



Data from additional studies of adefovir dipivoxil in a variety of patient populations, including those with lamivudine-resistant HBV, patients with compensated and decompensated liver disease, post-liver transplant patients and patients co-infected with HBV and HIV, also were presented at AASLD in November 2001, and further data will be presented at EASL in April 2002.



To date, Gilead has provided access to adefovir dipivoxil through Study 435 to approximately 400 patients with lamivudine-resistant chronic HBV infection who are wait listed for or have received a liver transplant. Adefovir dipivoxil is an investigational compound and has not yet been determined safe or efficacious in humans for its ultimate intended use.



Chronic Hepatitis B Virus Infection

Worldwide, there are approximately 350 million chronic carriers of HBV, of which approximately one million die each year from complications of the disease, making chronic HBV infection one of the 10 most common causes of death. Complications of chronic HBV infection include cirrhosis (scarring of the liver), liver failure and primary liver cancer (hepatocellular carcinoma).



Patients infected with the precore mutant strain of HBV may be predisposed to more severe and progressive liver injury. Precore mutant HBV infects up to approximately 50 percent of the 350 million chronic HBV carriers worldwide and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30-80 percent of chronic HBV patients are estimated to be infected with this strain.



Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has five marketed products and focuses its research and clinical programs on anti-infectives, including antivirals, antifungals and antibacterials. Headquartered in Foster City, CA, Gilead has operations in the United States, Europe and Australia.



03/13/02



Source

Gilead Sciences. Gilead Initiates Early Access Program for Adefovir Dipivoxil, Investigational Treatment for Chronic Hepatitis B Infection. Press Release. March 13, 2002.

www.gilead.com



References

Y Benhamou and others. Adefovir Dipivoxil 10 mg Suppresses HBV Viral Replication in HIV/HBV Co-Infected Patients with Lamivudine Resistant HBV. Abstract 123 (oral). Program and Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. March 24-28, 2002. Seattle, WA.



Y Benhamou and others. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open label pilot study. The Lancet 2001; 358: 718-23. September 1, 2001.



C Lai and others. New England Journal of Medicine 1998; 339:61-68.