By Jennifer Van Brunt
Editor
Regulatory agencies around the globe are setting records for the rate at which they are beginning to approve new drugs for treating two of the world's most insidious and prevalent diseases infections caused by hepatitis viruses B and C. Taken together, or individually, these two viruses pose a major threat. They have already infected hundreds of millions of individuals worldwide.
An approved therapy for hepatitis B and C viruses has been available for some years. But alpha-interferon has nasty side effects and limited therapeutic efficacy. It's estimated that only about 20 to 40 percent of chronically infected individuals actually respond to treatment.
But the drug arsenal has now been bolstered by the addition of several new products to attack the hepatitis viruses. These include the nucleoside analogue Epivir, which has proven so successful in treating HIV infection and AIDS; and Rebetron, a drug that pairs alpha-interferon and a (different) synthetic nucleoside with broad-spectrum antiviral activity.
The Scope Of The Problem
The hepatitis viruses are a deadly lot, striking their victims silently and often lying in wait for decades before they destroy their unsuspecting hosts. Often, by the time an individual realizes that he or she is infected, that person's liver is already entering advanced stages of cirrhosis. Hepatitis infections if they manifest at all in the early stages can present a series of mild flu-like symptoms. They can go undiagnosed or misdiagnosed.
By itself, hepatitis B virus is credited with infecting upwards of 350 million people a full 5 percent of the world's population. One-third of those individuals who carry this virus will develop serious progressive liver disease, which eventually culminates in cirrhosis, cancer and death. In fact, this one virus is the ninth most common cause of death in the world.
The vast majority of individuals infected with HBV about 75 percent live in Asia and the Pacific Rim, but there are also a significant number in the U.S. According to Atlanta's Centers for Disease Control and Prevention (CDCP), there are more than 1 million carriers in the States, and only a very small percentage have been treated.
Hepatitis C virus (HCV) is no poor relation, either. Worldwide, there could be close to 60 million chronically infected individuals and 300 million carriers. On a global basis, 50 to 80 percent of infected individuals eventually develop serious disease. In fact, HCV is the leading cause of liver cancer in the People's Republic of China. But it's also achieved that status in the U.S., where the CDCP estimates that about 4 million Americans are chronically infected with HCV. Of those, a full 70 percent go on to develop chronic liver disease and 8,000 to 10,000 succumb every year. The CDCP also predicts that HCV infection will continue to rise in the U.S., with three times as many people infected by the year 2010. Grimly, the number of deaths caused by HCV will then surpass those caused by the AIDS virus.
Recent Approvals
On Dec. 9, the FDA approved Epivir-HBV (lamivudine) tablets and oral solution for treating adults with chronic hepatitis B virus infection. The product, created by Laval, Quebec, biotech firm BioChem Pharma Inc. (NASDAQ:BCHE) and licensed to London-based Glaxo Wellcome plc, is the same chemical entity that has been approved for treating HIV, but administered in a lower dose. It's administered once a day, and is apparently the first oral medication for treating HBV infection to hit the market. Sales of Epivir for treating HIV infection are already nearing the C$1 billion mark; in 1997, its second full year on the market as an HIV treatment, Epivir racked up worldwide sales of C$973 million (US$632 million). Now that it's been approved for treating HBV, this one drug in its various guises could double those numbers to become the all-time biotech best-seller. Epivir (or 3TC) is a nucleoside analogue that acts to interfere with viral replication.
The same drug was approved on Nov. 30 for marketing in Canada, where it will be sold under the name Heptovir. It's also been approved in the Philippines, New Zealand and Pakistan. In the Asian market, it is called Zeffix. And Glaxo Wellcome (NYSE:GLX) has filed for marketing approval in more than 30 other countries.
On Dec. 9, the FDA also approved Schering-Plough Corp.'s (NYSE:SGP) combination therapy Rebetron for hepatitis C virus infection in treatment-naïve patients (those with compensated liver disease previously untreated with alpha-interferon therapy). A mere six months before, on June 3, the FDA approved Rebetron for use in HCV-infected patients with compensated liver disease who have relapsed following alpha-interferon treatment.
The product consists of Rebetol capsules (ribavirin; a synthetic nucleoside with broad-spectrum antiviral activity that Madison, N.J.-based Schering-Plough licensed from ICN Pharmaceuticals Inc. [NYSE:ICN], of Costa Mesa, Calif.) and Schering-Plough's Intron A (recombinant interferon alfa-2b), taken as an injection.
While alpha-interferon is intended to stimulate the immune system to fight off viral invaders, other products are also aimed at this end. Of those, SciClone Pharmaceuticals Inc.'s (NASDAQ:SCLN) Zadaxin is the furthest along the commercial trail. The product, thymosin alpha 1, is a synthetic version of the naturally occurring peptide hormone thymosin. On Dec. 16, the San Mateo, Calif., company announced that it had received approval to market Zadaxin for both HBV and HCV infections in Cambodia. It also got approval for the product in Mexico, but here the indication is for use as an influenza vaccine adjuvant. Approvals in Mexico for treating both HBV and HCV should soon follow, according to the company.
But Zadaxin has already been approved for treating chronic HBV infection in the People's Republic of China, Kuwait, Myanmar (formerly Burma), Peru, the Philippines and Singapore. Marketing applications for this indication are pending in a further 21 countries. It is approved for treating HCV in the Philippines, as well. SciClone's partner in Japan, Schering-Plough KK, has initiated Phase III trials in hepatitis B and Phase II studies in hepatitis C. Zadaxin is also in advanced clinical trials as a combination therapy with alpha-interferon (for HCV infection) and the nucleoside analogues famciclovir and lamivudine (for HBV infection).
Plenty Of Clinical Efforts
The clinical efforts of biotech companies and big pharma firms for finding effective viral therapies especially for hepatitis B virus have also begun to mount. Those highlighted in the last two months include the following:
* In early December, PowderJect Pharmaceuticals plc (LSE:PJP), based in Oxford, U.K., and corporate collaborator Glaxo Wellcome reported results from a Phase I trial of a prophylactic DNA vaccine for treating HBV infection. It's intended to elicit a protective immune response, which has been backed up by the very early results. The DNA vaccine encodes the surface antigen of HBV, and it is delivered to the skin as a dry powder using PowderJect's needle-free delivery system.
* Foster City, Calif.-based Gilead Sciences Inc.'s (NASDAQ:GILD) antiviral product adefovir dipivoxil is in late-stage clinical trials for treating chronic HBV. The drug, a reverse transcriptase inhibitor, has been configured in an oral, once-daily dosage form. To date, the clinical results have indicated that the product has reduced levels of HBV in patients by 99.99 percent; also, the antiviral drug is apparently active against all known clinically relevant strains of HBV.
* Nabi (NASDAQ:NABI) is also developing a product, termed H-BIG, which is a reformulated version of hepatitis B immune globulin (human), for preventing reinfection of transplanted livers in patients with chronic HBV infection. The Boca Raton, Fla., company filed an expanded-access investigational new drug application in November. The product license application (PLA) for the intramuscular formulation of this drug is currently under review by the FDA for post-exposure prophylaxis of HBV disease; Nabi submitted the PLA in August 1998.
* London-based Medeva plc (NYSE:MDV) and partner Janssen Pharmaceutica International are also in the clinic with a treatment for chronic HBV infection. This product, called Hepagene, is billed as an immunotherapeutic vaccine; it's a third-generation recombinant vaccine that incorporates all three HBV surface antigens. In mid-December, the companies reported results from an early clinical trial being conducted in the Pacific Rim. As well, Medeva submitted a Pan-European license application for Hepagene in October 1998.
* Triangle Pharmaceuticals Inc. (NASDAQ:VIRS), of Durham, N.C., is also testing an antiviral nucleoside, FTC, as a treatment for HBV infection. The company presented preliminary data from a Phase I/II trial in mid-November.
* Pharmaceutical giant Bristol-Myers Squibb Co. (NYSE:BMY), of Princeton, N.J., is developing lobucavir, its own oral formulation of a broad-spectrum nucleoside analogue for treating HBV. In early November, the company launched large-scale, international Phase III clinical trials in patients with chronic HBV infection. *
Holiday Notice