Hepatology—the study of liver diseases—representsa clinically important, dynamic, and lucrative arena ofpharmaceutical development. The opportunity in this

therapeutic sector stems from the growing population of pa-tients worldwide afflicted by common liver ailments suchas viral hepatitis (including hepatitis C and hepatitis B) andnonalcoholic fatty liver disease (NAFLD). Several unmettherapeutic needs within each of these liver injuries con-stitute major opportunities for drug development. This ar-ticle focuses on hepatitis C, hepatitis B, and NAFLD, whichare arguably of greatest commercial relevance to the phar-maceutical industry.

Hepatitis CEpidemiology. Recent Centers for Disease Control and Pre-vention, Rockville, MD, (CDC) data indicate that approximate-ly 4.1 million Americans (1.3% of the U.S. population) carrythe hepatitis C virus (HCV), 3.2 million of whom are chroni-cally infected. Between 10,000 and 12,000 deaths annuallyare attributed to HCV-associated liver disease; end-stage liver disease associated with chronic HCV provides thelargest demand for liver transplantation. In the United States,the major routes of HCV transmission occur through intra-venous drug usage, exposure to contaminated blood prod-ucts, and solid organ transplantation. Although the U.S. in-cidence rate has fallen since the 1980s owing to such factorsas advances in screening the blood supply, a growing de-mand for HCV therapy exists as more chronically infectedpatients present with advanced liver disease and thus be-come treatment candidates.

Current Treatment. The standard-of-care approach totreating chronic HCV involves a combination of pegylated

interferon (PEG-INF) (available as Pegasys from Roche Lab-oratories, Nutley, NJ, or Peg-Intron from Schering-Plough,Kenilworth, NJ) plus ribavirin (RBV) (available as Copegusfrom Roche or Rebetol from Schering-Plough), administeredbased upon the genotype of the patient. Patients with geno-type 1—the more frequently-occurring genotype—receive48 weeks of PEG-INF plus RBV. Patients with genotypes 2or 3, the less common genotypes, undergo treatment for 24weeks.

Key Trends and Unmet Needs. The two major trends in thetreatment of HCV include: (1) an expansion of treatment can-didates as a function of more patients with chronic HCV pre-senting with advanced liver disease and (2) the potential re-treatment of patients who have not responded to previoustherapeutic options as a function of the availability of nov-el medications, noted below. The main unmet therapeuticneeds in the treatment of HCV reside in the domains of bothefficacy and tolerability. Treatment with PEG-INF plus RBVinvolves a considerable burden of adverse effects, most no-tably influenza-like symptoms, neuropsychiatric effects, andhematological abnormalities.

Medications in Development. Numerous medications arein development for HCV. Viramidine (taribavirin, ValeantPharmaceuticals International, Alisa Viejo, CA), Telaprevir(VX-950, Vertex Pharmaceuticals, Inc., Cambridge, MA), Val-opicitabine (NM 283, Idenix Pharmaceuticals, Inc., Cam-bridge, MA), SCH 503034 (Schering-Plough Corporation), GS-9132 (Gilead Sciences, Inc., Forest City, CA), and Albuferon(albumin-interferon alfa-2a, Human Genome Sciences,Rockville, MD, and Novartis International AG, Basel,Switzerland) may reach the marketplace earliest. Among thenew medications, industry experts expect the protease andpolymerase inhibitors to considerably improve rates of re-sponse and potentially truncate the length of treatment, es-pecially in the more difficult-to-treat patients.

Researchers as also developing IDN-6556 (Idun Pharma-ceuticals, Inc., recently acquired by New York City–basedPfizer Inc), a novel small-molecule caspase protease in-hibitor that inhibits apoptosis (programmed cell death),

Noah M. PinesExecutive Vice PresidentGfK V2Blue Bell, Pennsylvania

Hepatology Is an Important New Frontier inPharmaceutical DevelopmentLiver diseases represent an important field of new drug development due to the unmetneeds of patients with these illnesses. This article describes both these unmet needs andareas of opportunity to develop new compounds for common liver ailments.

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implicated in the generation of fibrosis. The agent is alsobeing evaluated in hepatitis B, primary biliary cirrhosis(PBC), and nonalcoholic steatohepatitis (NASH). Selectedanti-HCV therapies in development are found in the Table.

Hepatitis BEpidemiology. Worldwide, hepatitis B (HBV) is the mostcommon viral illness. According to the CDC, 2 billion peo-ple have been infected with HBV, 360 million are chronical-ly infected, and approximately 600,000 individuals die eachyear from HBV-related liver disease or hepatocellular car-cinoma. An estimated 1.25 million Americans chronicallycarry HBV, and between 4,000 and 5,000 annual deaths at-tributed to chronic liver disease are caused by HBV.

From 1990 through 2002, the incidence of acute HBV fell67%, from more than 21,000 per year to approximately 8,000per year. Analysts attribute this drop to the availability of anHBV vaccine. The major routes of HBV transmission includeexposure to contaminated blood (e.g., transfusion and intra-venous drug use), vertical transmission (mother to child), sex-ual contact, and household and occupational exposure.

Treatment. The standard of care in the treatment of HBV in-volves one of two approaches. The original paradigm in-volved interferon (INF) therapy, Intron A from Schering-Plough Corporation. Most patients, however, currentlyreceive therapy through small-molecule oral antiviral med-ications. Treatment options for HBV include oral nucleotideanalogs or nucleoside analogs such as Gilead Sciences,Inc.’s Hepsera (adefovir), Bristol-Myers Squibb’s Baraclude(entecavir) or GlaxoSmithKline (GSK’s) Epivir-HBV (lamivu-dine). The FDA also approved Roche Laboratories’ Pegasysand Schering-Plough Corporation’s Intron A (interferon

alfa-2b) for the treatment of HBV; infourth quarter of 2006, Tyzeka (telbivu-dine/LdT), an oral nucleoside analog fromIdenix Pharmaceuticals and NovartisPharmaceuticals, was approved.

Key Trends. As a result of Epivir-HBV’shigh rates of resistance, a utilization shifthas occurred in recent years from Epivir-HBV to Hepsera and Baraclude, both ofwhich are associated with less develop-ment of resistance over time. In the future,treatment options may shift toward com-bination therapy as a strategy to perpet-uate the activity of current drugs by pre-venting the onset of viral resistance.

Another important trend to consider inthe management of HBV is the possibleexpansion of potential treatment candi-dates to encompass those with elevatedHBV virus and normal liver enzyme lev-

els (i.e., “immune-tolerant” patients). Currently, HBVtreatment guidelines only recommend the treatment of pa-tients with elevated liver enzymes. However, a recent studydemonstrated that patients with a detectable HBV viralload are at higher risk for developing liver cancer.

Unmet Needs. Unmet therapeutic needs in the treatment ofHBV relate to treatment efficacy, resistance, and durationof therapy. Rates of HBe antigen seroconversion, a keymarker of therapeutic success in patients who haveHBeAg-positive disease, remain relatively modest. In addi-tion, curing a patient with hepatitis B is extremely rare.

Preventing antiviral resistance remains another unmetneed in HBV treatment. As noted earlier, the growth in an-tiviral resistance drives physicians toward a combination-therapy approach.

Medications in Development. Several small-molecule antiviral agents are in development for the treatment of HBV.They include Gilead Sciences, Inc.’s Viread (tenofovir) andTruvada (a once-daily fixed dose combination of Viread andEmtriva [emtricitabine/FTC]); valtorcitabine from IdenixPharmaceuticals, Inc.; clevudine from Pharmasset, Inc.(Princeton, NJ); and pradefovir, which was recently was ac-quired by Schering-Plough Corporation.

Nonalcoholic Fatty Liver DiseaseEpidemiology. Nonalcoholic fatty liver disease is predict-ed to become the most common liver disease in the future.It describes an accumulation of excess fat in the liver to theextent that fat cells constitute 5% to 10% of the total weightof the organ. The disease is a direct result of the compo-nents of metabolic syndrome (i.e., obesity, type 2 diabetes

TABLE: SELECT ANTI-HCV THERAPIES IN DEVELOPMENT

Drug Category Drug Name and Sponsor FDA Status

Interferons Albuferon (Human Genome Sciences) Phase 2Multiferon (Viragen, Inc.) Phase 2Medusa interferon (Flamel Phase 2Technologies S.A.)

Rebif (Ares Serono) Phase 3Ribavirin Viramidine (Valeant Pharmaceuticals) Phase 3Alternatives Merimepodib (Vertex Phase 2

Pharmaceuticals, Inc.)Amantadine (Endo Laboratories, etc.) Phase 3

Immunomodulators Zadaxin (SciClone Pharmaceuticals, Inc.) Phase 3Ceplene (Maxim Pharmaceuticals, Inc.) Phase 2E1 vaccine (Innogenetics NV) Phase 2IC-41 (Intercell) Phase 2VX-950 (Vertex Pharmaceuticals, Inc.) Phase 2

Antifibrotics ISIS-14803 (Isis Pharmaceuticals, Inc.) Phase 2IP-501 (Indevus Pharmaceuticals, Inc.) Phase 3

Others ID-6556 (Idun Pharmaceuticals, Inc.) Phase 2

HCV = Hepatitis C virus.

mellitus, dyslipidemia, and/or hypertension), or it may resultfrom long-term usage of such medications as corticos-teroids or antiretrovirals.

When patients become afflicted with nonalcoholicsteatohepatitis (NASH), a condition caused when the liverbecomes inflamed as a result of NAFLD, the inflammationresulting from the excess fat leads to the damage or destruc-tion of liver cells. According to the American Liver Founda-tion, New York City, 10% to 20% of Americans have NAFLDand 2% to 5% have NASH.

Current Treatment. No approved orcommonly accepted medications areavailable for the treatment of NAFLD/NASH. Practitioners generally urgepatients to lose weight by adopting alow-carbohydrate, low-fat diet to at-tain better control of their diabetes,and/or to address their dyslipidemiaand hypertension.

Unmet Needs. Aside from a dearth oftherapeutic options for the treatment of NAFLD/NASH, a keyunmet need resides in the availability of noninvasive modesof assessing patients’ liver status on an ongoing basis, andthus determining which patients are progressing fromNAFLD to NASH. Liver biopsy prevails as the gold standard,but it is costly, painful, and subject to error. A second unmetneed surfaces in the gastroenterology community’s under-standing of the natural course of NAFLD and NASH, espe-cially an understanding of which patients with NASH willprogress, and thus eventually may require treatment.

Medications in Development. As a function of the associa-tion between insulin resistance and NAFLD, most of the agentsunder investigation for treating NAFLD/NASH are insulin-sensitizing antidiabetic agents. These include metformin and

the thiazolidinediones (TZDs), including both Avandia (rosigli-tazone) from GSK and Actos (pioglitazone) from Eli Lilly andCompany. The liver toxicity heritage of this class, however,does raise some concern; troglitazone was removed from themarket because of acute idiopathic hepatitis. Aside from theTZDs, other agents that are being or have been consideredfor NASH include Merck & Co., Inc.’s Cozaar (losartan), Trental (pentoxifylline) from Sanofi-Aventis (Bridgewater, NJ),ursodeoxycholic acid, and sulfasalazine.

ConclusionLiver disease represents a major newresearch and development frontier forthe pharmaceutical industry as a func-tion of the recognition and growth of viral hepatitis and NAFLD combinedwith the relative scarcity of effectiveand tolerable treatment options. Al-though numerous potential liver con-ditions exist—including viral hepatitis,metabolic liver injury, alcoholic liverdisease, PBC, autoimmune hepatitis,

hemochromatosis, primary sclerosing cholangitis, and Wilson’s disease—HCV, HBV, and NAFLD/NASH presentlyrepresent the most commercially inviting targets for drugdevelopment. !

Noah M. PinesExecutive Vice PresidentGfK V2587 Skippack PikeBlue Bell, Pennsylvania 19422Phone: (215) 283-3200, ext. 364E-mail: npines@gfkv2.com www.gfkv2.com

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Liver disease represents a majornew research and

development frontier for the pharmaceutical

industry.

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