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Clinical Trials, HDV, Hepatitis D Drug Development, Hepatitis Delta (HDV), Liver, Liver Health, Research

Drug Profile: Three Hepatitis Delta Therapies That We Hope to See Widely Available Soon

 

 

 

 

The full extent of hepatitis delta’s (HDV) global disease burden is still unknown and treatment options for HDV have been limited. However, there are three promising up-and-coming drugs to treat HDV patients. This blog post details the drugs’ current phase of development and testing, how well they work for patients in the real world, and their current path toward regulation and market availability. 

Bulevirtide (Hepcludex) 

Gilead Sciences Inc. has been seeking approval from the U.S. Food and Drug Administration (FDA) for bulevirtide, or Hepcludex, since 2021. In 2020, Gilead acquired MYR, a German pharmaceutical company that had developed the hepatitis delta virus (HDV) drug. At the time that it was acquired, Hepcludex had already been conditionally authorized for use in Germany, France, and Austria (MYR Pharmaceuticals, 2020). Gilead, which is based in California, in the U.S., hoped to accelerate the global launch of Hepcludex. Since then, however, Hepcludex remains in regulatory limbo. In October 2022, the FDA announced the rejection of Hepcludex, citing concerns around the manufacturing and delivery of the drug. Gilead responded by stating that they plan to resubmit Hepcludex for approval as soon as possible (Dunleavy, 2022). Six months after the FDA rejection, the Committee for Medicinal Products for Human Use, which is the European Medicines Agency’s (EMA’s) committee responsible for conveying its opinions on medicinal products to the public, stated that it recommends Hepcludex for full marketing authorization in Europe. Since its conditional approval, a Phase 3 trial (which utilized data from patients in Germany, Italy, Russia, Sweden, and the U.S.) has shown it to be safe and effective for HDV patients. If the European Commission fully approves Hepcludex, it will be the only authorized HDV treatment available in Europe (Dunleavey, 2023).  

Lonafarnib 

At the end of 2022, Eiger Biopharmaceuticals announced that lonafarnib reached an important milestone in its phase 3 trial.  

The trial includes two regimens in patients with chronic HDV:  

  1. 1. Lonafarnib boosted with ritonavir, a protease inhibitor, which interferes with the ability of certain enzymes to break down proteins, often used in combination with other therapies for antiviral activity (this is an all-oral therapy), and
  2. 2. Lonafarnib in combination peginterferon alfa, an antiviral and immunosuppressive, which either completely or partially suppresses the immune system, often used to treat hepatitis B (HBV) and hepatitis C (HCV) patients (this is a combination therapy).

Both treatment arms showed statistical significance over the placebo arm of the trial. The placebo arm is used as a control in drug testing and has no therapeutic effect on patients. The results showed three noteworthy findings: 1. After 48 weeks (about 11 months) of treatment with the all-oral regimen, a small number of patients may achieve reduced viral load and improved liver function. 2. Combining lonafarnib and ritonavir with peginterferon alfa showed the potential to almost double the effectiveness of the drugs. 3. Combination treatment may lead to significant liver tissue improvement. Researchers found that most adverse symptoms related to treatment were either mild or moderate in severity, with gastrointestinal issues being the most frequent (Eiger Biopharmaceuticals, 2022). 

Peginterferon Lambda 

In June 2023, the results of a phase 2 trial looking at the safety and efficacy of peginterferon lambda (also an Eiger Biopharmaceuticals product) in HDV patients were published. Previously, peginterferon lambda showed a good tolerability profile (or the degree to which patients can tolerate negative treatment symptoms) in patients with HBV and HCV when compared to peginterferon alfa. In this trial, patients received 120-mcg or 180-mcg peginterferon lambda injections over 48 weeks, followed by 24 weeks of post-treatment follow-up. Researchers found that 180-mcg injections were more effective in HDV patients compared to the 120-mcg injections group. Results showed that with 48 weeks of 180 mcg treatment, patients showed a significant reduction in HDV RNA, the molecules responsible for perpetuating the virus in HDV patients. 36% of patients’ HDV RNA levels were undetectable. Some of the adverse symptoms patients experienced were flu-like symptoms and elevated transaminase levels, or enzymes that are related to a fatty liver. Most adverse symptoms were mild or moderate in nature and were resolved without additional treatment (Etzion et al, 2023). 

These three drug therapies show promise for HDV patients. Hepcludex is well on its way to becoming fully authorized in Europe after its three-year conditional approval and recent Phase 3 trial results. Lonafarnib’s phase 3 trial results are encouraging and Eiger, its manufacturer, plans to begin meeting with regulatory agencies, such as FDA and EMA, to discuss regulatory submissions (Eiger Biopharmaceuticals, 2022). Peginterferon lambda has shown a higher tolerability in patients with a lower adverse event rate than peginterferon alfa, which has been modestly used for the treatment of HDV over the past several decades (Etzion et al, 2023). Peginterferon lambda still has a ways to go before regulatory discussions, considering that results have just been published from its Phase 2 trial. Typically, in Phase 2 trials, researchers seek to learn whether the treatment they are studying is effective in fighting the disease. Phase 3 will test whether peginterferon lambda is more effective than already available, standard treatments. Hopefully, these three drugs continue to show positive results for HDV patients and will become widely available over the next few years. There are a number of other HDV drugs currently in development, but these are still in the early stages of clinical trial testing. You can stay up to date on the latest developments of these drugs by checking out the Hepatitis Delta Connect Drug Watch page. 

Dunleavy, K. (2022, October 28). Gilead hits surprise FDA rejection for hepatitis D drug already authorized in Europe for 2 Years. Fierce Pharma. https://www.fiercepharma.com/pharma/gilead-gets-fda-rejection-hepatitis-d-drug-already-authorized-europe-two-years 

Dunleavy, K. (2023, May 5). After FDA rejection, Gilead’s Hepcludex looks set for full EU NOD. Fierce Pharma. https://www.fiercepharma.com/pharma/gileads-hdv-drug-hepcludex-gets-thumbs-chmp 

Eiger announces both lonafarnib-based treatments in pivotal phase 3 D-LIVR trial in Hepatitis Delta virus (HDV) achieved statistical significance against Placebo in composite primary endpoint. Eiger BioPharmaceuticals. (n.d.). https://ir.eigerbio.com/news-releases/news-release-details/eiger-announces-both-lonafarnib-based-treatments-pivotal-phase-3 

Etzion, O., Hamid, S., Lurie, Y., Gane, E. J., Yardeni, D., Duehren, S., Bader, N., Nevo-Shor, A., Channa, S. M., Cotler, S. J., Mawani, M., Parkash, O., Dahari, H., Choong, I., & Glenn, J. S. (2023). Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial. Hepatology (Baltimore, Md.), 77(6), 2093–2103. https://doi.org/10.1097/HEP.0000000000000309  

MYR Pharmaceuticals. (2020, September 17). Myr Pharmaceuticals launches HEPCLUDEX® in Germany, France and Austria. PR Newswire: press release distribution, targeting, monitoring and marketing. https://www.prnewswire.com/news-releases/myr-pharmaceuticals-launches-hepcludex-in-germany-france-and-austria-301133006.html 

HDV, Hepatitis D Avocacy, Hepatitis Delta (HDV), Research

Why Is Hepatitis Delta So Hard to Eliminate?

Forty-five years after Mario Rizzetto discovered the hepatitis D virus (also known as HDV or hepatitis delta), scientists and advocates met for the first ever Delta Cure Meeting to discuss new scientific trends and global advocacy efforts to eliminate this difficult-to-treat disease. This conference included topics ranging from HDV’s global prevalence to new diagnostic methods, and the need for specific and improved efforts to fight this virus.

During the Delta Cure Meeting, scientists called for new global strategies to find people living with HDV and have prompted the World Health Organization (WHO) to update their screening guidelines to include HDV tests for all people living with hepatitis B (people who are HBsAg-positive). 

Unfortunately, some barriers continue to stand in the way of making this call to action a reality. Dr. Meg Doherty, the Director of Global HIV, Hepatitis, and STI Programmes at the WHO, stated in a recent Healio article that the WHO does not have any prevention recommendations that are specific to HDV. However, the WHO is developing updated guidance for HDV testing, diagnosis, and treatment as a part of hepatitis B (HBV)-focused elimination efforts.

While some initial progress has been made, (such as the inclusion of HDV in the 2022-2030 Global Health Sector strategies, which aim to increase knowledge about infections like HIV and viral hepatitis to create effective responses to and advance elimination efforts for these diseases), there is a need to expand elimination strategies to include HDV more broadly. The lack of robust inclusion of HDV disregards people who are currently living with HBV and are at the highest risk of HDV exposure and acquisition. People who have been diagnosed with HDV are overlooked as linkage to appropriate care, diagnostics and treatments (which are important for people living with HDV to stay healthy) continues to be out of reach for many. One of the major challenges with HDV is also the lack of testing and surveillance to identify those individuals living with delta and to understand the true burden of the disease. 

The WHO affirms that HDV elimination efforts must start with raising awareness of the virus and increasing advocacy efforts. The scientists at the Delta Cure Meeting are doing just that. Here are some solutions that scientists and researchers have identified to address the challenges surrounding HDV elimination:

Barrier: Overly complicated screening guidelines present a major barrier to the elimination of HDV. It was only in March 2023 that the Centers for Disease Control and Prevention (CDC) introduced new guidelines recommending universal HBV screening for all adults in the United States. A recommendation for universal HDV reflex testing (automatic testing for HDV when one tests positive for HBV) for all individuals living with HBV has still not been implemented in the US. Additionally, the American Association for the Study of Liver Diseases (AASLD) has screening guidelines for HDV that are still risk-based, meaning that only people who have certain risk factors are recommended to be tested for HDV (high-risk groups include people who inject drugs and men who have sex with men, among others). Conversely, the European Association for the Study of the Liver (EASL) and the Asian-Pacific Association for the Study of the Liver (APASL) have moved away from risk-based screening. Both EASL and APASL recommend that providers perform the HDV antibody total (anti-HDV total) test in all HBsAg-positive patients to identify whether someone has recovered from or is currently infected with delta antibodies (Palom et al., 2022; Hepatitis B Foundation, 2023).

Risk-based screening burdens both providers and patients alike. As part of risk-based testing, providers must ask questions about risk factors that are not necessarily part of a regular health screening and must know which factors indicate a need for HDV testing. Providers are often hesitant to ask their patients these questions, as talking about risk factors can be uncomfortable and overwhelming. But if providers do not ask, then the patient must know their own risk factors and ask for the test themselves (which can be very uncomfortable). A guideline to test everyone who is positive for hepatitis B (HBsAg-positive) for HDV would eliminate this confusion and hesitation. In light of this barrier, and the fact that risk-based testing is not evidence-based, the Hepatitis B Foundation recommends that all people living with HBV ask their doctors about getting tested for hepatitis delta.

Call to Action: Introduce new screening guidelines, including screening all adults who are HBsAg-positive for HDV. As the US does not have universal HDV screening guidelines, people who test positive for the hepatitis B surface antigen (HBsAg) but do not fall into a “high risk” category are not recommended to be screened for HDV, so they may be living with hepatitis delta and unaware of their infection. This puts these individuals at a much higher risk of having unmanaged hepatitis delta and developing liver cirrhosis or other advanced liver diseases at a more rapid pace. HBV is also already significantly underdiagnosed in the US and, as Dr. Nancy Reau neatly summarized “If you aren’t thinking about B, you’re not thinking about D.” 

Barrier: HDV is not a nationally notifiable or reportable condition in the United States. This means that healthcare providers are not required to report cases of HDV to local and state health departments or to the CDC. Because of this, the actual number of people living with HDV in the US remains underestimated, and without accurate prevalence data, prioritization of this neglected disease is made all the more difficult. 

Call to Action: Make HDV a reportable and notifiable disease in the US and beyond. Dr. Doherty of the WHO agrees that efforts to identify the populations most at risk for HDV are needed in the fight for HDV elimination, and specifically mentions the need for epidemiological surveys (different study designs of various sizes to better understand the burden of disease). A new survey method was discussed at the 2022 Delta Cure Meeting by Dr. Saeed Hamid in his presentation, “Epidemiology of HDV: From Low to High Endemic Countries.” Dr. Hamid called for new national surveys to be distributed to people with advanced liver disease because this population is one in which HDV is most likely to be found. He believes this monitoring method can be used in any country to advance elimination efforts.

Barrier: There are currently no standard HDV diagnosis methods, which makes HDV elimination very difficult to achieve. Professor Maurizia Brunetto, who presented “Diagnosis of HDV: Clinical Virology and New HBV Biomarkers,” explained that there is likely an underestimation of HDV infection in general, due to misdiagnosis (when someone is incorrectly diagnosed) and challenges accessing the diagnostic testing for hepatitis delta. When Dr. Doherty of the WHO was asked about what needs to be done to improve HDV elimination efforts (specifically in the US), she mentioned improving diagnostic testing tools.

Call to Action: Simplify testing and introduce point-of-care testing to increase HDV detection and diagnosis. Prof. Brunetto explained that point-of-care testing (getting rapid results within 20 minutes of being tested rather than waiting for up to 48 hours for results of a traditional blood test) can improve overall HDV diagnostics around the world. She believes it is especially important to introduce point-of-care testing in countries with less developed medical infrastructure. Having this point-of-care testing method will be easier to maintain and can identify people living with HDV earlier and link them to treatment before their disease becomes more severe. Dr. Stephen Urban, who led the discovery and creation of the first ever drug for HDV (bulevirtide), has been developing a point-of-care test to find delta antibodies from one single drop of blood. While only in the experimental phase, Dr. Urban and colleagues have published two journal articles that provide evidence for the test’s potential effectiveness in identifying people living with HDV (Lempp et al., 2021). While still more than two years away from using this method at a larger scale, Dr. Urban believes that this method can lead to faster HDV diagnostics.

As new HBV screening guidelines are introduced and new diagnostic tools are being developed, we have to advocate for universal HDV screening in individuals with hepatitis B by raising public awareness of the importance of screening and raising the voices of people who are living with HDV around the world. 

References

American Association for the Study of Liver Diseases [AASLD]. (2021, November). Hepatitis d (delta) at AASLD 2021.  https://www.natap.org/2021/AASLD/AASLD_136.htm 

Centers for Disease Control and Prevention [CDC]. (n.d.). Interpretation of hepatitis B serologic test results [Fact Sheet]. U.S. Department of Health & Human Services. https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf 

CDC. (2022). Nationally notifiable diseases. U.S. Department of Health & Human Services. https://www.cdc.gov/healthywater/statistics/surveillance/notifiable.html 

CDC. (2023, March 10). Screening and testing for hepatitis B virus infection: CDC recommendations — United States, 2023. MMWR | Recommendations and Reports, 72(1);1–25. https://www.cdc.gov/mmwr/volumes/72/rr/rr7201a1.htm?s_cid=rr7201a1_w 

Delta Cure. (2022, October). Program. https://www.deltacure2022.com/pages/program/index.php 

Delta Cure. (2022, October). Poster Exhibition. https://www.deltacure2022.com/pages/posterExhibition/index.php 

European Association for the Study of the Liver. (2017, April 17). EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. Journal of Hepatology, Clinical Practice Guidelines, 67(2), P370-398. DOI: https://doi.org/10.1016/j.jhep.2017.03.021

Hepatitis B Foundation [HBF]. (2023). Testing and diagnosis. https://www.hepb.org/research-and-programs/hepdeltaconnect/testing-and-diagnosis/ 

HBF (2023). Treatment. https://www.hepb.org/research-and-programs/hepdeltaconnect/treatment/ 

Lempp, F. A., Roggenbach, I., Nkongolo, S., Sakin, V., Schlund, F., Schnitzler, P., Wedemeyer, H., Le Gal, F., Gordien, E., Yurdaydin, C., & Urban, S. (2021). A Rapid point-of-care test for the serodiagnosis of hepatitis delta virus infection. Viruses, 13(12), 2371. https://doi.org/10.3390/v13122371 

Michael, E. (2022, October 31). Q&A: Expert discusses current state of hepatitis D, challenges in elimination efforts. Healio. https://www.healio.com/news/hepatology/20221031/qa-expert-discusses-current-state-of-hepatitis-d-challenges-in-elimination-efforts 

Palom, A., Rando-Segura, A., Vico, J., Pacin, B., Vargas, E., Barreira-Diaz, A., Rodriguez-Frias, F., Riveiro-Barciela, M., & Esteban, R. (2022, October). Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D. Journal of Hepatology, 4(10), 100547. https://doi.org/10.1016/j.jhepr.2022.100547 

Sarin, S. K., Kumar, M., Lau, G. K., Abbas, Z., Chan, H. L., Chen, C. J., Chen, D. S., Chen, H. L., Chen, P. J., Chien, R. N., Dokmeci, A. K., Gane, E., Hou, J. L., Jafri, W., Jia, J., Kim, J. H., Lai, C. L., Lee, H. C., Lim, S. G., Liu, C. J., … Kao, J. H. (2016). Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update. Hepatology International, 10(1), 1–98. https://doi.org/10.1007/s12072-015-9675-4

TheBMJ. (n.d.). Chapter 5. Planning and conducting a survey. https://www.bmj.com/about-bmj/resources-readers/publications/epidemiology-uninitiated/5-planning-and-conducting-survey

World Health Organization. (2022, July 18). Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022-2030. https://www.who.int/publications/i/item/9789240053779 

HDV, Hepatitis D Drug Development, Hepatitis Delta (HDV), Research

What You Need to Know About the 2022 Liver Meeting and How It Relates to Hepatitis Delta

 

 

 

 

This year, the annual Liver Meeting, hosted by the American Association for the Study of Liver Diseases (AASLD), was held in Washington, D.C. The featured presentations included new innovations in liver transplant surgery, disease modeling (which is a process that uses cells to show how a disease develops and to test possible treatment approaches), and drug development. While an effective, functional cure for hepatitis B virus (HBV) is still 5-10 years away, researchers, scientists, healthcare providers, and people with lived experience all came together and agreed that more needs to be done to reduce the burden of liver diseases and improve health outcomes now. One highlight of the meeting was Dr. Francis Collins, former director of the U.S. National Institutes of Health and special advisor to President Biden, hosting a special session to introduce a national hepatitis C elimination plan for the U.S. Unfortunately, this plan is focused on hepatitis C. As a response, the Hepatitis B Foundation will soon send an advocacy letter pushing for the inclusion of hepatitis B and hepatitis delta in this plan. Make sure you are signed up for our Action Center alerts to stay engaged with hepatitis B advocacy efforts.

Of particular note at this year’s meeting were the presence of many patient advocates and people with lived experience, and an increased focus on hepatitis delta. One important hepatitis delta poster presentation was delivered by Dr. Tatyana Kushner of Mount Sinai Hospital in New York City, entitled “HDV Patient Perspective: The Impact of Disease and Current Unmet Needs.” By including the perspectives of people living with hepatitis delta virus (HDV), this study aimed to empower the patient community. Dr. Kushner and her colleagues collected data on people’s quality of life to identify unmet needs, barriers and gaps in HDV care (including disease management and access-to-care inequities).

The researchers found that a person’s care is affected in two ways: In the care they receive for their clinical diagnosis and their emotional journey after diagnosis. The participants’ experience of care was often negatively impacted by having a delayed HDV diagnosis, and limited access to specialized care and tolerable treatment options. Findings describe that the lack of specific and acceptable treatment options for hepatitis delta left people with little hope, which put an emotional burden on their life post-diagnosis. Due to the gaps in providers’ knowledge of HDV, participants held little trust in their healthcare providers. The study participants also shared that they suffered emotionally due to the stigma attached to their diagnosis.

Dr. Kushner and her colleagues call for an increased effort to educate healthcare providers on hepatitis delta, as their lack of HDV-specific knowledge drives health disparities or differences between groups, where one group is more burdened by a disease than the other. These are driven by unequal opportunities to achieve good health (CDC, 2020). Health disparities are preventable, and educating providers is the first step to overcoming these inequalities. Educating providers on HDV will lead to more rapid identification of the disease, as they will have a better understanding of the signs, symptoms and risk factors for hepatitis delta. Increasing advocacy efforts for point-of-care testing for both HBV and HDV in the U.S. will increase levels of testing and earlier identification of people at risk for the diseases. Timely diagnosis allows for people to be linked to specialty care earlier, ultimately improving health outcomes. Improving community awareness of HDV will combat stigma and likely reduce testing hesitancy, which can improve health outcomes. The researchers call for drug developers to meet the needs of the patient community by developing tolerable and hepatitis delta-specific treatments.

In terms of drug development, researchers presented on antiviral treatments for people living with HDV and discussed preferred outcomes of treatment, based on what they believed to be most helpful to each individual’s physical health. To understand these treatment considerations, it is important to review how HDV functions. Hepatitis delta virus (HDV) uses a person’s RNA (ribonucleic acid) to produce and replicate the virus, so high HDV RNA levels in the blood indicate severe infection, and low or undetectable HDV RNA levels indicate that the virus is not rapidly reproducing (Stephenson-Tsoris & Casey, 2022). A virological response is defined as a long-term period of low-level replication that leads to undetectable HDV RNA levels in the blood six months after stopping treatment, and this indicates viral suppression (Yamashiro et al., 2004). A biochemical response is defined as normalization of alanine aminotransferase (ALT) levels after antiviral treatment (Kim et al., 2022). When liver cells are damaged, they release ALT into the bloodstream, so high levels of ALT indicate that one’s liver is diseased or damaged (MedlinePlus, n.d.). ALT normalization is considered a good indicator that antiviral therapy is working because it means that there is less liver damage, liver disease is less severe, and people living with HBV/HDV are at less risk of harm (Kim et al., 2022).

One study of interest from the meeting was the D-LIVR study by Eiger BioPharmaceuticals, Inc.: Lonafarnib Global Study in Chronic Hepatitis Delta. This study consisted of 400 participants, who were all on treatment for 48 weeks, then followed up with researchers 24 weeks after treatment. In total, 50 participants received pegylated interferon (Peg IFN) treatment for 48 weeks; 125 participants received a combination of Lonafarnib, Ritonavir and Peg IFN; and 175 participants received the oral antiviral therapy Lonafarnib and Ritonavir. There were also 50 people on a placebo treatment. A placebo is a harmless pill that has no effect on a person, and is often used in clinical trials to test the effectiveness of a specific treatment being studied, in this case, Peg IFN, Lonafarnib and Ritonavir (Harvard Health Publishing, 2021). The researchers decided that they wanted to see a decline in HDV RNA (virologic response) and normalization of ALT (biochemical response) at week 48 as their study’s main outcome or proof that the treatment could work. In this study, an acceptable virologic response was defined as a “2log decline of HDV RNA levels,” which means they wanted to see HDV RNA levels decrease by 99% from the original levels that were measured before starting treatment (Wikipedia, n.d.).

Pegylated interferon (Peg IFN) is a protein-based medication that prompts the body to activate its natural immune system (induce innate antiviral response) (Zhang & Urban, 2021; Drugbank, n.d.). For Peg IFN-based treatments, researchers determine that undetectable HDV RNA six months after stopping treatment is desirable. However, researchers emphasize the importance of yearly HDV RNA post-treatment screening to monitor for viral relapses after treatment. For long-term treatment (over 48 weeks), a 99% reduction of HDV RNA concentration levels is an appropriate virologic response for non-interferon-based treatments, but more studies must be done to establish whether a person living with hepatitis delta is actually benefiting from the treatment (this is called clinical benefit). When establishing the clinical benefits for non-interferon-based treatments (or any new treatment), researchers can measure delays in disease progression or improvement of signs and symptoms of the disease, which includes symptom relief, improved functioning and improved survival rates (Lee, n.d).

Based on a variety of extensive studies (not just D-LIVR), the researchers decided to combine virologic and biochemical responses to try to demonstrate the clinical benefit of using ongoing antiviral treatment as a functional cure for hepatitis delta. They concluded that acceptable endpoints for HDV treatment studies include undetectable HDV RNA six months after stopping treatment, the loss of the hepatitis B surface antigen (HBsAg), and ALT normalization in people living with chronic hepatitis delta. This can also be considered a functional cure since there are undetectable levels of HBsAg and HDV RNA in the blood for a sustained period of time, even after finishing treatment (Wong et al., 2022).

While there is still time before we overcome the burden of hepatitis delta, the presentations from The Liver Meeting show us that researchers and scientists are constantly working to improve the lives of people living with hepatitis delta. Development toward a functional cure is progressing, and advocates are incorporating peoples’ lived experiences and perspectives into drug development and education. Collaboration between all these groups is the best way to move forward in the fight against hepatitis delta.

For more information on hepatitis delta, you can visit the Hepatitis Delta Connect website or review this hepatitis delta fact sheet.

References

Centers for Disease Control and Prevention. (2020). Health disparities. Centers for Disease Control and Prevention, Division of Adolescent and School Health, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. https://www.cdc.gov/healthyyouth/disparities/index.htm 

Drugbank. (n.d.). Peginterferon alfa-2a. Drugbank. https://go.drugbank.com/drugs/DB00008

Harvard Health Publishing. (2021, December 13). The power of the placebo effect. Harvard Health Publishing, Harvard Medical School. https://www.health.harvard.edu/mental-health/the-power-of-the-placebo-effect 

Kau, A., Vermehren, J., & Sarrazin, C. (2008). Treatment predictors of a sustained virologic response in hepatitis B and C. Journal of Hepatology, 49(4), 634-651. https://doi.org/10.1016/j.jhep.2008.07.013

Kim, S. H., Cho, E. J., Jang, B. O., Lee, K., Choi, J. K., Choi, G. H., Lee, J. H., Yu, S. J., Kim, Y. J., Lee, Y. B., Yoon, J. H., Kim, J. W., Jeong, S. H., & Jang, E. S. (2022). Comparison of biochemical response during antiviral treatment in patients with chronic hepatitis B infection. Liver International: Official Journal of the International Association for the Study of the Liver, 42(2), 320–329. https://doi.org/10.1111/liv.15086 

Lee, J. (n.d.). Defining Clinical Benefit in Clinical Trials: FDA Perspective [Presentation]. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. https://celiac.org/main/wp-content/uploads/2015/04/great3-07.pdf 

MedlinePlus. (n.d.). ALT blood test. National Library of Medicine (U.S.). [updated August 3, 2022]. https://medlineplus.gov/lab-tests/alt-blood-test/ 

Raman, S. (2022 October 25). Administration eyes national hepatitis C treatment plan. Roll Call: Policy. https://rollcall.com/2022/10/25/administration-eyes-national-hepatitis-c-treatment-plan/ 

Stephenson-Tsoris, S., & Casey, J. L. (2022). Hepatitis delta virus genome RNA synthesis initiates at position 1646 with a nontemplated guanosine. Journal of Virology, 96(4), e0201721. https://doi.org/10.1128/JVI.02017-21 

Wikipedia. (n.d). Log reduction. https://en.wikipedia.org/wiki/Log_reduction

Wong, G. L. H., Gane, E., & Lok, A. S. F. (2022). How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?. Journal of Hepatology, 76(6), 1249–1262. https://doi.org/10.1016/j.jhep.2021.11.024

Yamashiro, T., Nagayama, K., Enomoto, N., Watanabe, H., Miyagi, T., Nakasone, H., Sakugawa, H., & Watanabe, M. (2004). Quantitation of the level of hepatitis Delta virus RNA in serum, by real-time polymerase chain reaction—and its possible correlation with the clinical stage of liver disease. The Journal of Infectious Diseases, 189(7), 1151–1157. https://doi.org/10.1086/382133

Zhang, Z., & Urban, S. (2021). New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. Journal of Hepatology, 74(3), P686-699. https://doi.org/10.1016/j.jhep.2020.11.032

Clinical Trials, HDV, Hepatitis D Drug Development, Hepatitis Delta (HDV), News, Research

Results from Hepatitis Delta Clinical Trials Announced at International Liver Congress 2022

London, UK was the host city for this year’s annual International Liver Congress (ILC), the yearly meeting of the European Association for the Study of the Liver (EASL), which took place from June 22nd-26th. This meeting provides an opportunity for those working to address liver diseases around the world to gather in one location and exchange ideas, present research, and work to advance diagnosis, prevention, treatment, and elimination of these serious conditions. This year’s meeting saw significant attention given to hepatitis delta, as new treatments continue to move through the pipeline and more widespread approval for prescription of current treatments is sought. Below is a quick snapshot of some of the presentations!

The US-based pharmaceutical company Gilead Sciences, Inc. demonstrated with results from a Phase 3 clinical trial that treatment with Hepcludex (bulevirtide), the first medication ever approved for hepatitis delta (HDV), has been shown to achieve significant response in chronic HDV. After 48 weeks, 48% of study participants who received different doses of treatment with Hepcludex achieved virological response (meaning a decline in hepatitis delta viral load, ALT normalization, and a change in liver stiffness), compared to only 2% of those who had not received any treatment. When compared to results from clinical trials after 24 weeks, response rates to HDV only improved, showing the drug to be even more effective over time. Throughout the clinical trials, there have been no adverse events reported that are attributable to this treatment.

Hepcludex has also been found to have a positive impact on the quality of life of individuals living with hepatitis delta, and their overall ability to manage the condition. There were improvements found in health distress, performance of daily activities related to hepatitis, emotional impact of hepatitis, and ability to work. This data reinforces the efficacy and safety of Hepcludex and hopefully strengthens the case for approving the drug in more parts of the world.

“As the most severe form of viral hepatitis, HDV presents a significant disease burden with high healthcare-related costs and until recently, no approved treatment options,” said Heiner Wedemeyer, MD, Director, Clinic for Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, and principal investigator of the study. “These results presented at ILC 2022 not only highlight the important clinical role that bulevirtide has to play as a safe and effective treatment option for chronic HDV, but critically also demonstrate that with prolonged treatment, we can achieve higher response rates so we can better manage this rare, life-threatening disease in more people.”

Presently, Hepcludex has been conditionally approved by the European Commission for prescription in France, Germany, and Austria. It has not yet been approved by the United States Food and Drug Administration (FDA) or in other countries. A Biologics License Application was submitted by Gilead to the FDA in late 2021 for injection of 2mg of Hepcludex to treat adults with HDV and compensated liver disease. Hepcludex had previously been granted Breakthrough Therapy and Orphan Drug designations by the FDA and PRIority MEdicines (PRIME) scheme eligibility by the European Medicines Agency (EMA).

The second company to present their research findings at the ILC was US-based Eiger BioPharmaceuticals, Inc. The two primary hepatitis delta drugs that they have in the pipeline are called lonafarnib and peginterferon lambda. One abstract presentation indicated that peginterferon lambda (lambda) had better antiviral activity and tolerability than peginterferon alfa (the previous version of this drug that has been used as the only somewhat effective, but off-label treatment for hepatitis delta since the early 1980s). Lambda has been shown to block production of new hepatitis delta virus very effectively. Additionally, lambda in combination with lonafarnib was found to lower levels of HDV RNA and decrease its production and release, more effectively than lambda by itself. Patterns in HBV DNA, hepatitis B surface antigen, and ALT were also observed as part of this study. In its Phase 3 D-LIVR study, which is assessing the safety and efficacy of lonafarnib in combination with ritonavir, with and without peginterferon alfa, Eiger has assembled the largest cohort of global participants in an HDV study, and therefore the largest body of data. Results from this study are anticipated by the end of 2022.

The final piece of big hepatitis delta news to come out of the conference was the announcement from Vir Biotechnology Inc. that they are beginning a Phase 2 clinical trial for VIR-2218 in combination with VIR-3434 for the treatment of chronic hepatitis delta. Initial data from this study is anticipated in 2023.

Hepatitis delta is now receiving more attention than ever before and there is only more hope as new treatments are created, investigated, approved, and made available. For a complete overview of hepatitis delta, including basic information, resources, clinical trial opportunities, and a complete list of drugs that are in the pipeline, visit www.hepdconnect.org.

References

https://www.gilead.com/news-and-press/press-room/press-releases/2022/6/treatment-with-hepcludex-bulevirtide-meets-primary-endpoint-and-achieves-significant-response-in-chronic-hepatitis-delta-virus-at-48-weeks

https://www.streetinsider.com/Corporate+News/Vir+Biotechnology+Inc.+%28VIR%29+Announces+New+Clinical+Data+From+its+Broad+Hepatitis+B+Program/20256465.html

https://www.prnewswire.com/news-releases/eiger-biopharmaceuticals-announces-results-from-multiple-presentations-at-the-european-association-for-the-study-of-the-liver-easl-international-liver-congress-2022-301576119.html

HDV, Hepatitis D Avocacy, Hepatitis Delta (HDV)

Recent Roundtable Discussion Highlights Hepatitis Delta Virus

April 21st and 22nd, 2022 marked the occurrence of a roundtable meeting solely focused on hepatitis delta virus (HDV), which was jointly hosted by the American Liver Foundation and the Hepatitis B Foundation. This was one in a series of events taking place this year to raise the profile of hepatitis delta, a serious coinfection of hepatitis B virus (HBV) that is estimated to affect between 5 and 10% of people who are living with HBV. HDV is more severe than HBV alone, with a 70% chance of developing into cirrhosis or liver cancer if unmanaged, compared to an approximately 25% chance for those living with HBV alone. With approval of the first official treatment for hepatitis delta in Europe in July of 2020, expected approval in the United States later in 2022, and other treatments moving through the clinical trial pipeline, more is happening in the world of hepatitis delta than ever before. Despite the promising treatment landscape, the virus still remains significantly under-diagnosed (making estimation of true prevalence difficult), largely due to lack of awareness, low prioritization compared to other health conditions, and limited advocacy, and big questions persist about treatment equity, including access to knowledgeable providers, clinical trials, and available medications. The purpose of this roundtable was to begin a conversation among a diverse group of stakeholders about some of these issues, to bring attention to HDV and its potential consequences, to identify unmet needs in this area, and to prepare calls to action and next steps to address these needs.

Participants at the roundtable included individuals living with hepatitis delta, caregivers, healthcare providers, public health professionals, and representatives from community-based organizations. The conversation was very generative and really underscored some of the key issues that exist around hepatitis delta, including gaps in awareness and knowledge among medical and high-risk communities and limited access to and availability of HDV screening and care. These factors lead to under-diagnosis and under-surveillance, making the production of accurate data difficult, which in turn complicates advocacy efforts, since compelling data is often a key ingredient for policy change that might make screening, treatment, and linkage to care more available and accessible.

The ultimate planned outcome of this virtual event will be production of a white paper that will highlight key takeaways from the discussion, clearly outline unmet needs and priority issues for people living with HDV, and detail calls to action for stakeholders at every level to meet these needs and overcome some of the significant barriers and challenges that persist in diagnosing, managing, and treating HDV.

Another goal of the meeting was to begin to develop resources that can better support and engage the larger community around HDV awareness and advocacy – a first step toward this goal will be creation and dissemination of a visually appealing infographic, which will provide at-a-glance information about HDV and its estimated prevalence, transmission, prevention, testing, and treatment.

The white paper and infographic are expected to be complete by early summer 2022. The organizers of this roundtable meeting are hopeful that its outcomes will bring hepatitis delta virus more into focus for various stakeholder communities and generate more engagement and energy around this dangerous virus that has long been neglected and is not receiving the attention it deserves.

HDV, Hepatitis Delta (HDV), News, Research

Eiger Presents Clinical Trial Results at The Liver Meeting Digital Experience™ 2020

By Beatrice Zovich

The 2020 meeting of the American Association for the Study of Liver Diseases (AASLD) in November offered the opportunity for scientists from industry and academia to present their findings from clinical trials, studying new medications for hepatitis B and D. Two such presentations were given by Eiger BioPharmaceuticals, Inc. who presented their findings about how well their medications peginterferon lambda and lonafarnib work, both independently and in combination, to treat hepatitis delta virus (HDV) and halt liver fibrosis. The results are promising and offer hope for those affected by HDV.

The two medicines under investigation in these studies work in different ways. Lonafarnib works by blocking farnesyl transferase, an enzyme involved in prenylation, the modification of proteins that is necessary for the life cycle of HDV. Peginterferon lambda, on the other hand, triggers immune responses that are crucial for host protection during viral infections. Lambda can also target liver cells accurately, thus reducing the effects of inadvertently targeting central nervous system cells and making it more tolerable to those taking it (Eiger, 2020).

Eiger’s first study examined how well peginterferon lambda and lonafarnib (known as LIFT – Lambda InterFeron combo Therapy) work together to lower levels of HDV RNA, 24 weeks post-treatment (Eiger, 2020). This was a Phase 2 study. Lambda was administered at a dosage of 180 mcg once weekly, in combination with 50 mg of Lonafarnib and 100 mg of ritonavir given twice daily, for 24 weeks. The results of this study found that 77% of the 26 participants saw their HDV RNA levels decline and reach a level that was either undetectable or below the level of quantification. 23% of these participants were able to maintain these levels for 24 weeks after treatment had ended. Both tenofovir and entecavir were started prior to treatment for management of HBV. The observed side effects of this regimen were mild to moderate and included mostly gastrointestinal issues or were related to blood chemistry (Eiger, 2020).

The second study found that peginterferon lambda caused the regression of liver fibrosis after 48 weeks of treatment in people living with hepatitis delta. Two case studies emerged from the completed Phase 2 LIMT (Lambda Interferon MonoTherapy) study (Eiger, 2020). In these studies, a total of 33 participants received either 180 µg or 120 µg of lambda subcutaneous injections weekly for 48 weeks. Results indicated that degrees of liver fibrosis and levels of HDV RNA declined below the level of quantification in some participants, even after 72 weeks in a handful of cases. In some instances, ALT levels decreased as well. Side effects were found to be mild to moderate and fewer than those experienced by participants who had taken peginterferon alpha in the past. Side effects were primarily flu-like in nature (Eiger, 2020). 

Therapies for hepatitis B and D will only continue to improve and become more precise and targeted as time goes by. Check out the Hepatitis Delta Connect website for detailed information on HDV, as well as current clinical trials and a drug watch page, both of which are updated regularly. (A brand-new clinical trial has just been added!) For more information about Eiger BioPharmaceuticals, click here. 

References

Eiger BioPharmaceuticals, Inc. (2020, November 17). Eiger Announces Positive Peginterferon Lambda – Lonafarnib Combination End of Study Results from Phase 2 LIFT HDV Study in Late-Breaker Session at The Liver Meeting Digital Experience™ 2020. Retrieved December 30, 2020, from https://www.biospace.com/article/releases/eiger-announces-positive-peginterferon-lambda-lonafarnib-combination-end-of-study-results-from-phase-2-lift-hdv-study-in-late-breaker-session-at-the-liver-meeting-digital-experience-2020/

Eiger BioPharmaceuticals, I. (2020, November 16). Eiger Announces Case Studies Demonstrating Regression of Liver Fibrosis Following 48 Weeks of Therapy with Peginterferon Lambda in Patients with Chronic Hepatitis Delta Virus (HDV) Infection Presented at The Liver Meeting Digital Experience™ 2020. Retrieved December 30, 2020, from https://www.prnewswire.com/news-releases/eiger-announces-case-studies-demonstrating-regression-of-liver-fibrosis-following-48-weeks-of-therapy-with-peginterferon-lambda-in-patients-with-chronic-hepatitis-delta-virus-hdv-infection-presented-at-the-liver-meeting-digital–301173992.html 

HDV, Hepatitis B Research, Hepatitis Delta (HDV), News

New Hepatitis Delta Treatment Approved by European Commission

New Drug Approved for Treatment of Hepatitis Delta in Europe

A new drug to treat hepatitis delta has now been approved by the European Commission! The drug is called bulevirtide and will be marketed under the brand name Hepcludex. It was previously known at Myrcludex B. This approval follows a quarter century of research and development and is the first drug specifically for hepatitis delta approved in Europe. Due to the high prevalence of the hepatitis delta virus in Russia and the former Soviet Union, it has been approved for use there since the end of 2019, under the name Myrcludex. The European Medicines Agency recommended the drug for approval by the Commission at the end of May 2020 (German Center for Infection Research, 2020).

How Does It Work?

Hepcludex, developed by university researchers in Heidelberg, Germany, works as an entry inhibitor – that is, it prevents hepatitis delta virus (HDV) cells, and the hepatitis B virus (HBV) cells upon which HDV depends, from entering healthy liver cells. Both HDV and HBV cells are able to replicate and thrive exclusively in the liver because they need the bile acid transporter NTCP in order to do so. This transporter is the avenue through which HDV is received into the liver cell. Hepcludex works by blocking this reception process, so that the virus does not continue to infect healthy liver cells (German Center for Infection Research, 2020). The currently infected cells either die or are destroyed by the immune system.

How Have People Responded?

Hepcludex is an injectable medication given daily for 48 weeks. In phase I and II clinical trials, people seemed to respond well to this treatment. It seems that just a small amount of Hepcludex is needed, which is good news because it means that the normal processes of the bile salt transporter (NTCP – the receptor of the hepatitis delta virus) will not be widely disrupted (German Center for Infection Research, 2020). MYR Pharmaceuticals GmbH, which now has the license for Hepcludex, is currently in the process of running further phase II and larger phase III trials, in order to continue to determine long-term effects. Hepcludex has also been tested in combination therapy with PEG Interferon, which is administered weekly also via injection (Highleyman, 2019).

Does it also work for Hep B?

Right now, Hepcludex has been tested and works to treat people with hepatitis delta. Since hepatitis delta becomes the dominant virus in those co-infected with hepatitis B and hepatitis delta, clearing hep delta will not necessarily clear hep B as well. However, the curative properties of this drug for those only affected with hep B are being investigated, both alone and in combination with PEG interferon, and there was a loss of surface antigen (HbsAg) noted in 20% of clinical trial participants who were given this combination (Highleyman, 2019).

What does this mean for patients?

Research thus far indicates that Hepcludex can be more effective than interferon alone, the existing hepatitis delta treatment, which is usually not curative and has challenging side effects (Smith, 2020). Hepcludex is now available for prescription in Europe, although pricing schemes remain unclear. For updated information on pricing and availability, check with your doctor or visit the MYR Pharmaceuticals website here.

Clinical trials will continue to take place for this and other drugs. Researchers and pharmaceutical companies might experience difficulty in recruiting patients for hepatitis delta clinical trials because of a lack of awareness and testing – many people living with hepatitis delta worldwide remain undiagnosed. It is important for people at risk for hepatitis delta to be tested and linked to care if found to be infected. If you have hepatitis delta and are interested in participating in a clinical trial, you can search for one near you. To find a doctor to talk to about getting tested for hepatitis delta if you are living with hep B, click here. Hepatitis delta can often be managed and treated, and you are not alone! The most important first step is to know your status.

What does this mean for providers?

The exact number of people living with hepatitis delta around the world is unknown and estimates range anywhere from 20-70 million. Most of these individuals remain undiagnosed due in large part to a lack of testing and diagnostics. Stephan Urban, one of the researchers leading the effort in the development of Hepcludex has said that, in the United States, fewer than 5% of those tested for hepatitis B are also tested for hepatitis delta (Smith, 2020). It is true that in much of the world diagnostic tools remain unaffordable and so Dr. Urban and his team are developing a much less expensive and rapid test. If the capacity exists, however, testing is crucial for the management of this most severe form of viral hepatitis and all of the subsequent liver conditions that can develop from it. Additionally, as with all infectious diseases, vaccination of ALL people to prevent hepatitis B is critical. Click here for more information on hepatitis delta in general and here for questions and concerns.

References

German Center for Infection Research. (2020, August 5). First drug for hepatitis D has been approved by European Commission. EurekAlert! https://www.eurekalert.org/pub_releases/2020-08/gcfi-fdf080520.php

Highleyman, L. (2019, December 16). Combination therapies show promise against hepatitis D. Retrieved August 31, 2020, from https://www.worldhepatitisalliance.org/latest-news/infohep/3548132/combination-therapies-show-promise-against-hepatitis-d

Smith, J. (2020, August 20). Is Hepatitis D Healthcare Being Overlooked? LabioTech https://www.labiotech.eu/medical/hepatitis-d-ema-approval/

About Hepatitis B, HBV, HDV, Hepatitis B Awareness, Hepatitis Delta (HDV)

Know Your ABCs

What is Hepatitis?

Hepatitis simply means inflammation of the liver which can be caused by infectious diseases, toxins (drugs and alcohol), and autoimmune diseases. The most common forms of viral hepatitis are A, B, C, D, and E. With 5 different types of hepatitis, it can be confusing to know the differences among them all.

The Differences

While all 5 hepatitis viruses can cause liver damage, they vary in modes of transmission, type of infection, prevention, and treatment.

Hepatitis A (HAV) is highly contagious and spread through fecal-oral transmission or consuming contaminated food or water1. This means that if someone is infected with hepatitis A they can transmit it through preparing and serving food and using the same utensils without first thoroughly washing their hands. Symptoms of HAV include jaundice (yellowing of skin and eyes), loss of appetite, nausea, fever, abnormally colored stool and urine, fever, joint pain, and fatigue1. Sometimes these symptoms do not present themselves in an infected person which can be harmful because they can unknowingly spread the virus to other people. Most people who get HAV will feel sick for a short period of time and will recover without any lasting liver damage2. A lot of hepatitis A cases are mild, but in some instances, hepatitis A can cause severe liver damage. Hepatitis A is vaccine preventable and the vaccine is recommended for people living with hepatitis B and C. Read this blog post for a detailed comparison of hepatitis B and hepatitis A!

Hepatitis B (HBV) is transmitted through bodily fluids like blood and semen, by unsterile needles and medical/dental equipment and procedures, or from mother-to-child during delivery1. HBV is considered a “silent epidemic” because most people do not present with symptoms when first infected. This can be harmful to individuals because HBV can cause severe liver damage, including cirrhosis and liver cancer if not properly managed over time3. Hepatitis B can either be an acute or chronic infection meaning some cases last about 6 months while other cases last for a lifetime. In some instances, mostly among people who are infected as babies and young children, acute HBV cases can progress to a chronic infection3. Greater than 90% of babies and up to 50% of young children will develop lifelong infection with hepatitis B if they are infected at a young age.

Hepatitis C (HCV) is similarly transmitted like HBV through bodily fluids, like blood and semen, and by unsterile needles and medical/dental equipment and procedures. Symptoms of HCV are generally similar to HAV’s symptoms of fever, fatigue, jaundice, and abnormal coloring of stool and urine1, though symptoms of HCV usually do not appear until an infected individual has advanced liver disease. Acute infections of hepatitis C can lead to chronic infections which can lead to health complications like cirrhosis and liver cancer1. Read this blog for a detailed comparison of hepatitis B and hepatitis C!

Hepatitis Delta (HDV) infections only occur in persons who are also infected with hepatitis B1,3. Hepatitis Delta is spread through the transfer of bodily fluids from an infected person to a non-infected person. Similar to some other hepatitis viruses, hepatitis Delta can start as an acute infection that can progress to a chronic one. HDV is dependent on the hepatitis B virus to reproduce3. This coinfection is more dangerous than a single infection because it causes rapid damage to the liver which can result in fatal liver failure. Find out more about hepatitis B and hepatitis Delta coinfection here!

Hepatitis E (HEV) is similar to hepatitis A as it is spread by fecal-oral transmission and consumption of contaminated food and water1. It can be transmitted in undercooked pork, game meat and shellfish. HEV is common in developing countries where people don’t always have access to clean water. Symptoms of hepatitis E include fatigue, loss of appetite, stomach pain, jaundice, and nausea. Talk to your doctor if you are a pregnant woman with symptoms as a more severe HEV infection can occur. Many individuals do not show symptoms of hepatitis E infection1. Additionally, most individuals recover from HEV, and it rarely progresses to chronic infection. Read this blog for a detailed comparison of hepatitis B and hepatitis E!

Here is a simple table to further help you understand the differences among hepatitis A, B, C, D, and E.

Prevention

Fortunately, hepatitis viruses are preventable.

Hepatitis A is preventable through a safe and effective vaccine. The Centers for Disease Control and Prevention (CDC) recommend that children be vaccinated for HAV at 12-23 months or at 2-18 years of age for those who have not previously been vaccinated. The vaccine is given as two doses over a 6-month span1. This vaccine is recommended for all people living with hepatitis B & C infections

Hepatitis B is also preventable through a safe and effective vaccine. The vaccine includes 3 doses over a period of 6 months, and in the U.S. there is a 2-dose vaccine that can be completed in 1-month1,3. Read more here, if you would like to know more about the vaccine series schedule.

Hepatitis C does not have a vaccine, however, the best way to prevent HCV is by avoiding risky behaviors like injecting drugs and promoting harm reduction practices. While there is no vaccine, curative treatments are available for HCV1.

Hepatitis Delta does not have a vaccine, but you can prevent it through vaccination for hepatitis B1,3.

Hepatitis E does not have a vaccine available in the United States. However, there has been a vaccine developed and licensed in China1,2.

 

References

  1. https://www.cdc.gov/hepatitis/index.htm
  2. https://www.who.int/news-room/q-a-detail/what-is-hepatitis
  3. https://www.hepb.org/what-is-hepatitis-b/the-abcs-of-viral-hepatitis/

 

Hepatitis B Research, Hepatitis Delta (HDV)

Drug Update: Replicor Researchers Talk to HBF About Potential New Hep B and D Treatment

In October 2019, the Hepatitis B Foundation had the opportunity to speak with Andrew Vaillant, Ph.D., Chief Scientific Officer at Replicor at the annual International HBV Meeting in Melbourne, Australia. Dr. Vaillant gave us an inside look at REP 2139 – their drug candidate developed for the treatment of chronic hepatitis B and HBV/HDV coinfection. REP 2139 is a nucleic acid polymer that removes surface antigen (HBsAg) and as part of combination therapy, has achieved functional cure for chronic HBV (sustained HBsAg loss) and sustained clearance of HDV infection from the blood in early phase II proof of concept clinical trials it has completed to date. REP 2139 is currently in phase II of clinical trials. Below is Dr. Vaillant’s response to a series of questions we posed to him.

1. Replicor’s drug candidate REP 2139 is a nucleic acid polymer (NAP) for the treatment of chronic hepatitis B. Can you explain the mechanism for this drug and how it works?

REP 2139 is a polymer built from the building blocks the body uses to store genetic material in the body (nucleic acids). These building blocks are linked together in a unique pattern to form nucleic acid polymers (or NAPs for short) and in the case of REP 2139, use only naturally occurring nucleic acids and modifications to prevent it being recognized as a foreign molecule. As a result, REP 2139 is very well tolerated and safe in clinical trials.

In HBV infection, the most abundant viral antigen in the blood is the hepatitis B surface antigen (HBsAg) which plays an important role in preventing immune control of HBV. Circulating HBsAg is almost entirely in the form of non-infectious HBV subviral particles (SVP) which are produced independently from viral replication, making this viral antigen difficult to target with approved therapies. REP 2139 naturally enters liver cells (hepatocytes) and blocks the assembly of SVP in any hepatocyte producing SVPs. This mechanism effectively blocks the replenishment of HBsAg in the blood and also reduces HBsAg inside these hepatocytes. The overall antiviral effect of REP 2139 is to allow the body to clear HBsAg in order to reduce or remove the inhibition of immune control caused by this viral antigen.

2. REP 2165 is also mentioned as a drug candidate. Can you explain the difference between REP 2139 and REP 2165.

REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. More information about REP 2165 can be found under question 6.

3. Can you share the latest results from phase 2 trials? How is REP 2139 administered to patients, and for what duration of time? What kind of side effects can patients expect with REP 2139?

In our latest trials, side effects have been limited to mild effects from pegylated interferon (pegIFN). REP 2139 is currently given in a formulation (REP 2139-Mg) which results in little to no side effects during administration. REP 2139 is currently administered once every week for 48 weeks by intravenous infusion in combination with other antiviral agents. REP 2139-Mg is expected to be as effective with a once weekly injection under the skin (subcutaneous injection) which will be used in future trials.

4. Is REP 2139 equally effective in HBeAg positive and negative patients?

REP 2139 is effective in HBeAg positive and in HBeAg negative patients in multiple genotypes. As REP 2139 targets a host protein involved in SVP formation and not the virus or SVP directly, its antiviral effects are expected to be similar in all HBV genotypes and may also be effective in the presence of other co-infections with HBV such as HCV and HIV.

5. Can REP 2139 be safely used in patients with cirrhosis?

Another of the remarkable features of NAP based therapy is the high rate of flares in liver transaminases during therapy (occurring in almost all participants in the REP 401 study). Patients with these flares had no symptoms or any negative impact on their liver function.

Continually expanding evidence in the field tells us that during treatment of HBV, these flares are signs of elimination of HBV infection from the liver and are not accompanied by changes in liver function. These same features appear to hold true for transaminase flares during NAP therapy and, when occurring in the absence of HBsAg in the blood, are highly correlated with functional cure in our clinical trials. The ability of cirrhotic patients to tolerate these flares will be tested in future trials and we are encouraged by recent results (produced by a different group) with pegIFN in HBV / HDV co-infected patients showing that host mediated transaminase flares may also be well tolerated in cirrhotic patients.

6. Do you anticipate combination therapy will be needed? Will combination therapy include immune modulators like pegylated interferon and/or treatment with antivirals?

Replicor’s latest REP 401 study is the first in the field to feature triple combination therapy: Tenofovir disoproxil fumarate (TDF), pegIFN and either REP 2139-Mg or REP 2165-Mg. REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. In addition to the excellent control of HBV DNA with TDF exposure, this triple combination therapy for 48 weeks led to meaningful HBsAg decline (greater than a 10-fold reduction from baseline) in 90 % of participants, HBsAg clearance to very low levels similar to HBsAg “negative” in the qualitative test used in the United States (< 0.05 IU/mL) and HBsAg seroconversion (often with very high titers of anti-HBs antibodies) in 60% of participants. After removal of all treatment (including TDF), a 48-week follow-up yielded very encouraging results: 89% had normal liver function, 56% had reduced liver inflammation, 39% had stable virologic control and an additional 39% had functional cure with HBsAg seroconversion. These results illustrate the effectiveness of combining potent HBsAg reduction with immunotherapy but also suggest that direct acting antivirals such as TDF and entecavir may also contribute to establishing functional cure in a combination setting.

7. Surface antigen loss is key to people living with chronic HBV. Do you believe REP 2139 can provide a functional cure for chronic HBV?

In an early clinical study using NAPs alone, HBsAg clearance by itself resulted in virologic control (low level infection with normal liver infection no longer requiring therapy under current guidelines ) or functional cure (complete control of HBV DNA and HBsAg) persisting after removal of all therapy only in a small proportion of patients but stable throughout a 5 year follow-up. Importantly, HBsAg clearance with REP 2139 in a subsequent study led not only to a dramatic improvement in the activity of various immunotherapies (including pegIFN) but to virologic control occurring in a larger proportion of patients after removal of therapy persisting throughout more than 2 years of follow-up. As a result of these early studies, Replicor believes that the best approach to achieving functional cure of HBV infection is to simultaneously combine potent HBsAg reduction using REP 2139 with immunotherapy to restore effective and long-lasting immune control.

8. Which countries do you anticipate phase 3 trials to occur? Do you anticipate trials in the U.S?

Replicor believes that the combination of therapy with NUCs such as TDF and ETV, pegIFN and REP 2139-Mg will be the first available therapy to offer patients a real chance of eliminating the need for therapy and establishing functional control of their HBV infection and normalizing their liver function. Work is ongoing to start a phase II US trial in collaboration with the Aids Clinical Trials Group as soon as possible. We are also planning to assess other immunotherapies, the effectiveness of which we believe will be similarly improved with HBsAg clearance as we have demonstrated for pegIFN.

9. With regard to hepatitis delta, is there a difference in the mechanism for how it works?

REP 2139 is also potently active against HDV infection and is able to rapidly eliminate HDV RNA, normalize liver function and reverse the liver inflammation associated with HBV / HDV co-infection. The completed follow-up results from our long term follow-up study of co-infected participants treated with REP 2139 and pegIFN show complete control of HDV infection at 3.5 years follow-up in the absence of all therapy in a large proportion of patients. In many patients this control of HDV infection was associated with functional cure of HBV and in some patients with virologic control of HBV. This potent effect against HDV infection is assumed to be driven not only from the effect of REP 2139 on SVP (which also forms the envelope of the HDV virus) but on the ability of REP 2139 to interact with different forms of the hepatitis delta antigen protein essential for HDV replication and assembly.

Thank you to Dr. Vaillant for taking the time to talk to us about REP 2139. The results look promising! We look forward to learning more from continuing and new trials with REP 2139, used alone and in combination with antivirals and immune modulators. We know the hepatitis B virus is challenging, but those living with chronic HBV look forward to a day when there are therapies resulting in a durable loss of surface antigen and sustained viral suppression in a reasonable, finite amount of time. 

Hepatitis B Research, Hepatitis Delta (HDV)

Eiger BioPharmaceuticals: Developing Two New Hepatitis Delta Treatments

Eiger is currently working on two new drugs for hepatitis delta; Lonafarnib and Pegylated Interferon Lambda, which are both currently inphase 3 clinical trials. Lonafarnib is a new type of treatment that attempts to control hepatitis delta through a new method: through blocking a key enzyme that is needed for the hepatitis delta virus to replicate. Blocking this enzyme prevents a new virus from being created, which may control and even cure hepatitis delta.

Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Interferons work by stimulating the body’s own immune system to fight the virus. Pegylated interferon alpha, which is the only current treatment for hepatitis delta, is a difficult treatment to tolerate, with many patients experiencing unpleasant side-effects. Lambda utilizes the same method of treatment as IFN alfa, in combination with a new strategy, which stimulates an immune response and targets receptors in the liver, which may reduce side effects and result in improved tolerability.

Below is Eiger Biopharmaceuticals’ response to a series of questions we posed to them. 

Image courtesy of Praisaeng, at FreeDigitalPhotos.net.

1. Lambda is an immunomodulator and Lonafarnib is a prenylation inhibitor. Can you explain in laymen’s terms the mechanism for these drugs and how they work?

Eiger’s wording: Lonafarnib is a well-characterized, first-in-class, orally active inhibitor of an enzyme that is key to a vital process in the life cycle of HDV. Inhibiting this enzyme blocks the ability of HDV to assemble and package viral particles. Currently approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not affect HBsAg, and have no impact on HDV infection.

Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Lambda is a well-characterized, first-in-class, type III interferon (IFN) that stimulates immune responses that are critical for the development of host protection during viral infections. By targeting receptors that are localized in the liver, Lambda treatment may reduce side effects and result in improved tolerability .

Can you share, in simple terms, the basic results of Eiger phase 3 studies for hepatitis delta trials? Are these drugs equally effective in HBeAg positive and negative HBV patients?

The Eiger Phase 2 LOWR program with Lonafarnib has been completed. Over 120 patients were dosed in Phase 2 dose-finding studies to identify combination regimens of lonafarnib (LNF) and ritonavir (RTV) with and without pegylated interferon-alfa (PEG IFN α), with efficacy and tolerability to enable viral load suppression of HDV RNA and ALT normalization at Week 24.

  • Dosing regimens of LNF 50 mg twice daily + RTV 100 mg twice daily with and without PEG IFN-a-2a 180 mcg once weekly were identified with the following reported results:
    • All-oral: Lonafarnib boosted with ritonavir
    •  29% of patients achieved ≥ 2 log decline and ALT normalization
  •  Combination: Lonafarnib boosted with ritonavir + PEG IFN-a-2a
    •  63% of patients achieved ≥ 2 log decline and ALT normalization

These dosing arms are being further studied in the global Phase 3 D-LIVR study. Phase 2 studies have not been stratified by HBeAg status.

The D-LIVR Study, a Phase 3 pivotal trial, is on-going and evaluating the safety and efficacy of lonafarnib treatments in patients chronically infected with Hepatitis Delta Virus (HDV). Topline Week 48 data will be available in 2021.

2. How will Lambda and Lonafarnib be administered to patients?

Lonafarnib capsules are administered orally twice daily by mouth. Lonafarnib is taken in combination with ritonavir, a therapeutic booster that increases the bioavailability of lonafarnib. Ritonavir tablets are administered orally twice daily by mouth.

Pegylated interferon-lambda is administered as a self-administered subcutaneous injection once weekly.

3. Do you anticipate combination therapy will be needed and if so, which combinations do you anticipate?

No form of viral hepatitis has been cured with a single drug. Combinations of treatments with different mechanism of actions have always been required.

Lonafarnib and interferons have different mechanisms of action and have been studied as monotherapies and in combination together as treatments for HDV. While each treatment alone reduces the HDV viral load, combination studies have shown that using these treatments together leads to a synergistic effect and further reduces the HDV viral load.

Recently, the interim end of treatment results of peginterferon lambda (Lambda) and lonafarnib combination study in HDV-infected patients were presented at AASLD 2019. The LIFT study is being conducted within the National Institutes of Health (NIH) at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). LIFT is a Phase 2a open-label study of 26 adult patients with chronic HDV treated with Lambda 180 mcg once weekly in combination with Lonafarnib 50 mg twice daily boosted with ritonavir 100 mg twice daily for 24 weeks. Primary efficacy endpoint is > 2 log HDV RNA decline at end of treatment. At the time of analysis, 19 of 26 patients had reached Week 24. Median HDV RNA decline was 3.4 log IU/mL (IQR: 2.9-4.5, p<0.0001) with 53% (10 of 19) patients achieving below the limit of quantification and 37% (7 of 19) patients achieving undetectable HDV RNA at Week 24. 18 of 19 patients (95%) achieved primary endpoint of > 2 log decline during 24 weeks of therapy. We believe these data are the most encouraging yet in pursuit of HDV cure.

4. What kind of side effects can patients expect with Lambda and Lonafarnib, with or without combination therapy?

The most common side effects of lonafarnib include diarrhea, nausea, fatigue, decreased appetite, vomiting, abdominal pain, and decreased weight. Antacid, antiemetic, and antidiarrheal medications may be used prophylactically to treat these gastrointestinal side effects.

The most common side effects of pegylated interferon-lambda (Lambda) are the expected side effects of interferons. However, these side effects have been demonstrated to be much milder and less severe than what has been previously been shown with pegylated interferon-alfa (alfa). These include musculoskeletal (myalgia, arthralgia, and back pain), flu-like symptoms (chills, pyrexia, and pain) and elevated alanine aminotransferase (ALT) levels.

A combination of these side effects is expected with combination therapy.

5. Are Lambda and Lonafarnib safe for use in people with cirrhosis?

Currently, the safety and efficacy of lonafarnib and pegylated interferon-lambda are being investigated in persons chronically infected with HDV. The clinical trials require study participants meet certain eligibility criteria to be included in these studies. These eligibility criteria may or may not reflect the type of patient who will use these therapies after they receive FDA approval.

Phase 2 and Phase 3 studies both include patients with well-compensated cirrhosis.

6. With a clearance of HDV, would you also anticipate a loss of surface antigen – functional cure for chronic HBV as well? If so, in what percentage of HBeAg and HBeAb patients?

HDV is always found as a co-infection with HBV because HDV requires just a small amount of HBV surface antigen (HBsAg) to complete HDV viron replication. However, an HDV / HBV coinfection leads to much more severe chronic viral hepatitis compared to HBV monoinfection alone. Therefore, it is important to treat HDV, even if HBV is not cured. It is possible to clear HDV RNA without loss of HBsAg.

7. Lambda and Lonafarnib are currently in phase 3 trials for delta. Are you able to provide an approximate timeline for when it will be approved for use in U.S. and Europe?

Eiger BioPharmaceuticals is committed to developing safe and effective therapies for HDV and providing patients with a pathway to gain access to approved therapies as quickly as possible.

The D-LIVR Study is a global study that is evaluating the safety and efficacy of lonafarnib treatment in patients chronically infected with HDV. The D-LIVR Study is recruiting subjects in up to 20 countries in over 100 study sites. The D-LIVR study includes 48 weeks of treatment with two different lonafarnib-based treatment regimens, followed by 24 weeks of follow-up. Primary endpoint is ≥ 2 log decline and ALT normalization at Week 48. Topline data from the Phase 3 D-LIVR study will be available in 2021. For more information about study locations and eligibility, please visit www.clinicaltrials.gov  (NCT03719313).

End of Phase 2 meeting with FDA to discuss Phase 3 development with Lambda monotherapy is planned for Q1 2020.

Baruch S. Blumberg Institute