By Jennifer Van Brunt


Editor

Regulatory agencies around the globe are setting records for the rateat which they are beginning to approve new drugs for treating two of theworld's most insidious and prevalent diseases  infections caused by hepatitisviruses B and C. Taken together, or individually, these two viruses posea major threat. They have already infected hundreds of millions of individualsworldwide.

An approved therapy for hepatitis B and C viruses has been availablefor some years. But alpha-interferon has nasty side effects and limitedtherapeutic efficacy. It's estimated that only about 20 to 40 percent ofchronically infected individuals actually respond to treatment.

But the drug arsenal has now been bolstered by the addition of severalnew products to attack the hepatitis viruses. These include the nucleosideanalogue Epivir, which has proven so successful in treating HIV infectionand 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 silentlyand often lying in wait for decades before they destroy their unsuspectinghosts. Often, by the time an individual realizes that he or she is infected,that person's liver is already entering advanced stages of cirrhosis. Hepatitisinfections  if they manifest at all in the early stages  can presenta series of mild flu-like symptoms. They can go undiagnosed or misdiagnosed.

By itself, hepatitis B virus is credited with infecting upwards of 350million people  a full 5 percent of the world's population. One-thirdof those individuals who carry this virus will develop serious progressiveliver disease, which eventually culminates in cirrhosis, cancer and death.In fact, this one virus is the ninth most common cause of death in theworld.

The vast majority of individuals infected with HBV  about 75 percent live in Asia and the Pacific Rim, but there are also a significant numberin 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 onlya very small percentage have been treated.

Hepatitis C virus (HCV) is no poor relation, either. Worldwide, therecould be close to 60 million chronically infected individuals and 300 millioncarriers. On a global basis, 50 to 80 percent of infected individuals eventuallydevelop serious disease. In fact, HCV is the leading cause of liver cancerin the People's Republic of China. But it's also achieved that status inthe U.S., where the CDCP estimates that about 4 million Americans are chronicallyinfected with HCV. Of those, a full 70 percent go on to develop chronicliver disease and 8,000 to 10,000 succumb every year. The CDCP also predictsthat HCV infection will continue to rise in the U.S., with three timesas many people infected by the year 2010. Grimly, the number of deathscaused by HCV will then surpass those caused by the AIDS virus.

Recent Approvals

On Dec. 9, the FDA approved Epivir-HBV (lamivudine) tablets and oralsolution for treating adults with chronic hepatitis B virus infection.The product, created by Laval, Quebec, biotech firm BioChem PharmaInc. (NASDAQ:BCHE) and licensed to London-based Glaxo Wellcome plc,is the same chemical entity that has been approved for treating HIV, butadministered in a lower dose. It's administered once a day, and is apparentlythe first oral medication for treating HBV infection to hit the market.Sales of Epivir for treating HIV infection are already nearing the C$1billion 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). Nowthat it's been approved for treating HBV, this one drug in its variousguises could double those numbers to become the all-time biotech best-seller.Epivir (or 3TC) is a nucleoside analogue that acts to interfere with viralreplication.

The same drug was approved on Nov. 30 for marketing in Canada, whereit will be sold under the name Heptovir. It's also been approved in thePhilippines, New Zealand and Pakistan. In the Asian market, it is calledZeffix. And Glaxo Wellcome (NYSE:GLX) has filed for marketing approvalin 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-naïvepatients (those with compensated liver disease previously untreated withalpha-interferon therapy). A mere six months before, on June 3, the FDAapproved Rebetron for use in HCV-infected patients with compensated liverdisease who have relapsed following alpha-interferon treatment.

The product consists of Rebetol capsules (ribavirin; a synthetic nucleosidewith broad-spectrum antiviral activity that Madison, N.J.-based Schering-Ploughlicensed 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 tofight off viral invaders, other products are also aimed at this end. Ofthose, SciClone Pharmaceuticals Inc.'s (NASDAQ:SCLN) Zadaxin isthe 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 receivedapproval to market Zadaxin for both HBV and HCV infections in Cambodia.It also got approval for the product in Mexico, but here the indicationis for use as an influenza vaccine adjuvant. Approvals in Mexico for treatingboth HBV and HCV should soon follow, according to the company.

But Zadaxin has already been approved for treating chronic HBV infectionin the People's Republic of China, Kuwait, Myanmar (formerly Burma), Peru,the Philippines and Singapore. Marketing applications for this indicationare pending in a further 21 countries. It is approved for treating HCVin the Philippines, as well. SciClone's partner in Japan, Schering-PloughKK, has initiated Phase III trials in hepatitis B and Phase II studiesin hepatitis C. Zadaxin is also in advanced clinical trials as a combinationtherapy with alpha-interferon (for HCV infection) and the nucleoside analoguesfamciclovir and lamivudine (for HBV infection).

Plenty Of Clinical Efforts

The clinical efforts of biotech companies and big pharma firms for findingeffective viral therapies  especially for hepatitis B virus  have alsobegun 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 reportedresults from a Phase I trial of a prophylactic DNA vaccine for treatingHBV infection. It's intended to elicit a protective immune response, whichhas been backed up by the very early results. The DNA vaccine encodes thesurface antigen of HBV, and it is delivered to the skin as a dry powderusing 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 fortreating chronic HBV. The drug, a reverse transcriptase inhibitor, hasbeen configured in an oral, once-daily dosage form. To date, the clinicalresults have indicated that the product has reduced levels of HBV in patientsby 99.99 percent; also, the antiviral drug is apparently active againstall known clinically relevant strains of HBV.

* Nabi (NASDAQ:NABI) is also developing a product, termedH-BIG, which is a reformulated version of hepatitis B immune globulin (human),for preventing reinfection of transplanted livers in patients with chronicHBV infection. The Boca Raton, Fla., company filed an expanded-access investigationalnew drug application in November. The product license application (PLA)for the intramuscular formulation of this drug is currently under reviewby the FDA for post-exposure prophylaxis of HBV disease; Nabi submittedthe PLA in August 1998.

* London-based Medeva plc (NYSE:MDV) and partner JanssenPharmaceutica International are also in the clinic with a treatmentfor chronic HBV infection. This product, called Hepagene, is billed asan immunotherapeutic vaccine; it's a third-generation recombinant vaccinethat incorporates all three HBV surface antigens. In mid-December, thecompanies reported results from an early clinical trial being conductedin the Pacific Rim. As well, Medeva submitted a Pan-European license applicationfor Hepagene in October 1998.

* Triangle Pharmaceuticals Inc. (NASDAQ:VIRS), of Durham,N.C., is also testing an antiviral nucleoside, FTC, as a treatment forHBV infection. The company presented preliminary data from a Phase I/IItrial in mid-November.

* Pharmaceutical giant Bristol-Myers Squibb Co. (NYSE:BMY),of Princeton, N.J., is developing lobucavir, its own oral formulation ofa broad-spectrum nucleoside analogue for treating HBV. In early November,the company launched large-scale, international Phase III clinical trialsin patients with chronic HBV infection. *

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