Issue:October 2018

THERAPEUTIC FOCUS – Applying the HIV Treatment Model to Hepatitis B – Can a Cocktail Provide a Cure?


INTRODUCTION

In the ongoing search for a cure to hepatitis B, experts now believe that combining different drugs into a single regimen can work together against HBV and will be the most likely way to achieve a cure. Early trial results using this approach have been promising, and researchers are now turning up the heat in a race to find the right treatment combination.

Hepatitis B is an infectious disease that is caused by the hepatitis B virus (HBV). Affecting the liver and occurring in both acute and chronic modalities, patients who test positive for HBeAg, an HBV surface protein antigen, are said to be chronic and are at risk of developing liver disease if they test positive for more than 6 months.

According to the Hepatitis B Foundation, a national nonprofit organization focused on improving the quality of life and finding a cure for those affected by hepatitis B worldwide, the disease is the most common serious health threat in the world. It is considered up to 100 times more infectious than the human immunodeficiency virus (HIV) and is the primary cause of liver cancer, the second-leading cause of cancer deaths globally.

CHRONIC HEPATITIS B OVERVIEW

A 2016 report released by the National Academy of Sciences, Engineering and Medicine (NASEM) states that hepatitis B and C account for 78% of the world’s hepatocellular carcinoma cases and more than half of all fatal cirrhosis cases every year. Moreover, it surpassed HIV and AIDS to become the seventh leading cause of death in the world as recent as 2013.

The virus is transmitted by exposure to infectious blood or bodily fluid, and health officials estimate that 2 billion people have been infected with HBV, and an additional 10 to 20 million people become newly infected each year. Of these, an estimated 1 million people die each year from hepatitis B and related complications, such as liver cancer, according to the report. While Hep B is preventable by vaccination, once infected, there is no cure.

With limited efficacy of treatments for liver cancer and low survival rates, treatment targeting suppression of HBV replication before these complications arise is extremely important to increase longevity.

But there is some good news on the horizon. The NASEM report notes that the elimination of hepatitis B and C is now feasible due to development of new technologies.

FINANCIAL IMPACT

With such widespread infections, the economic burden to treat HBV runs in the hundreds of millions of dollars, based on a 2015 report from the National Institutes of Health.

The total annual cost for the active population of chronic hepatitis B patients and for those receiving treatment at various disease stages is estimated to be $450 million and $226 million, respectively, of which with 64% and 70% are allocated to direct costs, respectively, and 36% and 30% to indirect costs, respectively. It is worth noting that the dollars spent on drugs encompasses the largest proportion of the direct medical cost for all stages of the disease.

THE HIV MODEL

Knowing what we now know about other viral diseases, researchers believe that a cure for hepatitis B may be possible through the full eradication of the virus from the body (similar to hepatitis C) or what is known as a “functional cure,” whereby viral levels are minimal, and any negative effects are eliminated with continuous therapy by combining drugs with complementary mechanisms of action. If the latter sounds familiar, it’s because this approach is the breakthrough that transformed HIV from a certain death sentence to a manageable disease.

While still considered by the medical community to be one of the largest pandemics in the world, treatment of HIV has come a long way in a relatively short period of time. The earliest confirmed case of HIV in the US was in 1968, suggesting that HIV and AIDS (acquired immunodeficiency syndrome caused by HIV) was present in the US before 1966.

What we know is that hepatitis B isn’t a new disease. Researchers recently published findings in a science journal announcing they successfully reconstructed genomes from Stone Age and Medieval European strains of the hepatitis B virus. The recovery of the ancient virus’ DNA indicated that hepatitis B was circulating in Europe at least 7,000 years ago. Yet today, scientists are continuing to develop treatments and look for a cure.

Comparatively, it was just a year after AIDS was discovered, that researchers found HIV to be its cause and that the spread of the disease was due to people not knowing that they were infected with the deadly virus, much like it is today with hepatitis. Just two years later, multidrug therapies became widely available, and death rates began to decline. Highly active antiretroviral therapy (HAART), like Combivir, became the new treatment standard and saw the death rate decline by nearly 47%.

Today, there are more than 20 different options available, and the US FDA continues to clear new HIV medical products. And while not totally eradicated, a 2017 study has indicated that persons living with HIV who are being treated with antiretroviral therapy can reduce the virus to undectable levels in the blood that cannot transmit HIV to partners during sex. This brings us to the rationale that the same approach to HIV could work for hepatitis B.

THE HBV TREATMENT OPPORTUNITY

Currently, there are eight FDA-cleared drugs for the treatment of chronic HBV, including interferon-alpha, pegylated interferon-alpha, lamivudine, entecavir, telbivudine, adefovir dipivoxil, tenofovir alefanemide, and tenofovir disporoxil fumarate.

Despite these discoveries, a critical limitation of current therapies is the inability to achieve control of the infection in the vast majority of patients without lifelong treatment. This limited antiviral efficacy of currently approved HBV treatments highlights the need for new therapeutic tools for treating chronic HBV and underscores the need for combination therapy with new classes of agents.

Lamivudine, for example, often results in resistance development, with a 20% chance after 1 year and 70% chance after 2 years. Adefovir, on the other hand, has a much lower rate of resistance development, but has a lower level of potency against HBV. Various combinations of treatment have respective advantages and disadvantages, with none being ideal. Nucleoside analog (NA) therapy has advantages over interferon (IFN) therapy, including fewer side effects and easier administration. However, IFN therapy has the advantage of decreased frequency of resistance, and higher rates of HBeAg loss, but also disadvantages of high cost, limited patient response, and administration by injection with frequent side effects.

The drive to find meaningful combination therapy for the treatment of chronic HBV infection stems from the generally accepted principle that a functional cure should address the following:

-Reduction of HBV DNA

-Reduction in the production of viral proteins, including both s- and e-Antigens and protein X

-Reduction/elimination of cccDNA

-Stimulation of the immune response

Exemplifying this strategy is ContraVir Pharmaceuticals, a small biopharmaceutical company that is developing two novel anti-HBV compounds with complementary mechanisms of action.

BLAZING THE TRAIL OF HBV COMBINATION THERAPY

ContraVir’s HBV pipeline consists of two drug technologies. The first, tenofovir exalidex (or TXLTM) is the prodrug of a well-established anti-HBV nucleotide analog, tenofovir, marketed by Gilead as Viread®, which has been primarily developed to reduce HBV DNA.

The second, CRV431, is a cyclophilin inhibitor with a unique chemical structure that allows the cyclophilin inhibitor to have a wide therapeutic index; in other words, a drug that is highly potent against HBV while providing the potential for minimal toxicities.

The mechanisms of action of TXLTM and CRV431 are distinct and complementary to each other, inhibiting viral replication at multiple different points in the HBV life cycle. In clinical and preclinical studies, each drug has demonstrated unique properties that represent important advances in the treatment of HBV. However, layering CRV431 on top of TXLTM is a strategy that offers the potential to address this need for a combination therapy to target multiple stages of the HBV life cycle.

TXLTM is an antiviral drug that directly targets replication of the virus. It is designed to deliver high intracellular concentrations of the active antiviral agent of tenofovir. TXLTM’s novel structure results in decreased circulating blood levels of tenofovir, lowering systemic exposure, and thereby reducing the potential for renal and bone side effects.

According to the World Health Organization (WHO), the likelihood of developing a chronic hepatitis B infection is highly dependent upon the age when the infection occurs. The WHO reports that 80% to 90% of infants infected during the first year of life develop chronic infections and that 30% to 50% of children infected before the age of 6 develop chronic infections (less than 5% of otherwise healthy adults will develop chronic infection).

Knowing that chronic HBV infection is associated with significant morbidity and mortality if left untreated, the FDA granted Orphan designation for TXLTM for the treatment of Chronic Hepatitis B infection in the pediatric patient population. It is the only HBV treatment granted this designation for this group, and underscores the clinical importance of treating HepB in venerable chronically affected patients.

A new optimized formulation for TXLTM was recently announced, which will allow for more efficient, predictable, and precise delivery to the liver – where the virus resides. The next trial will characterize the pharmacokinetic profile of the new formulation in HBV patients and will indicate the target dose to be advanced into a Phase 3 registration clinical development program.

CRV431 has shown potential in experimental models to complement current hepatitis B treatments by reducing multiple markers of infection including HBV DNA, HBsAg, HBeAg, binding of HBx, and HBV active uptake by cells. Studies have also demonstrated that CRV431 decreases the progression of fibrosis in an animal model and also reduces both the number and size of liver tumors in a hepatocellular carcinoma (HCC) model. These latter two findings offer the potential to not only reduce the virus, but also minimize the impact of the virus on the downstream development of liver diseases.

Additionally and importantly, CRV431 is composed of a unique chemical structure that is known to be a highly potent “host-targeting” antiviral drug with a high selective index against HBV. The hepatitis B virus relies upon its host allowing the virus to propagate and thrive. An important host protein is called “cyclophilin,” and this protein participates in many steps of the HBV life cycle. CRV431 offers the potential to disrupt this important part of the HBV propagation cycle.

The safety and antiviral activity of CRV431 is built on a robust set of clinical data from chemically related cyclophilin inhibitors. Due to its immunosuppressive properties, naturally occurring cyclosporine A has been used for more than 30 years in the field of organ transplant, and cyclophilin inhibitors, such as alisporovir (developed by DebioPharm and acquired by Novartis), have achieved clinical safety and efficacy against hepatitis C virus. CRV431 has undergone extensive medicinal chemistry to shed its immunosuppressive activity and optimize its potency and target selectivity, which significantly increases its therapeutic window for treating hepatitis B.

Finally, pursuant to the acceptance of the Investigational New Drug (IND) application by the FDA and an agreement of an accelerated clinical program for CRV431, ContraVir recently announced the commencement of its Phase 1 in healthy volunteers.

These very significant developments serve to differentiate ContraVir as one of the few companies with two oral anti-HBV assets in clinical development.

SUMMARY

Overall, we believe the HBV market is poised for exceptional growth. As in HIV, it is going to take a combined effort to reduce or eliminate the threat that HBV has on society.

The drive to find meaningful combination therapy for the treatment of chronic HBV infections stems from the generally accepted principal that a functional cure should address the reduction of HBV DNA; reduction in the production of viral proteins, including both s-and e-Antigens and protein X, the reduction or elimination of cccDNA, and stimulation of the immune response.

This is a team effort. Researchers must continue to explore and master the science behind the disease, regulators need to be assured that developed treatments are safe and effective, and payors have to be willing to work with regulators and physicians to keep disease screening and treatment costs manageable so everyone has access to the cure.

Whatever the outcome, we know we are close to finding a cure for hepatitis B and believe we are at the dawn of a very bright future for HBV patients. It is no longer a question of if or how, but of when.

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James Sapirstein is CEO of ContraVir Pharmaceuticals, with more than 30 years of pharmaceutical industry experience. Mr. Sapirstein was the founding CEO of Tobira Therapeutics and also CEO of Alliqua prior to joining Contravir. Prior to Tobira, Mr. Sapirstein was the EVP – Metabolic and Endocrinology at Serono Inc. He served in the Global Marketing group at Gilead, beginning in 2000 where he led and developed the global marketing strategy for its flagship HIV drug, Viread®, and played a key role in the development of the drug combination strategy that resulted in Gilead’s acquisition of Triangle’s nucleoside portfolio. That acquisition ultimately led to the launch of Truvada, Gilead’s multibillion dollar combination HIV drug. He also spent his first 17 years in the large pharmaceutical company arena, where his last position was the Director of International Infectious Diseases Marketing at Bristol Myers Squibb.