Novel therapies spur renewed focus on HDV

Direct-acting antivirals for hepatitis C have dominated hepatitis research for the past decade and have revolutionized the treatment of HCV, but the emergence of new treatment options has put hepatitis D back in the spotlight.

“HDV is a disease that we are now refocusing on for multiple reasons,” Paul Y. Kwo, MD, FACG, professor of medicine and director of hepatology at Stanford University, told Healio. “Because of our advances and understanding of hepatitis B, we are developing novel therapies to try and improve functional cure rates for HBV, many of which will be effective for HDV as well.”

Paul Y. Kwo

HDV is unique and of particular importance in that it is the most severe form of viral hepatitis, causing higher rates of progression to cirrhosis and hepatocellular carcinoma. However, despite its aggressive nature, physicians currently do not have effective treatments, according to Kwo.

“The good news is that, on the horizon, we now have multiple therapies for HDV that, based on initial studies, look very promising and should allow us to offer better treatment options for our patients infected with HBV and HDV,” Kwo said.

Need for more effective therapies

Interferon alfa is the only licensed therapy currently utilized for treatment of HDV, with the most recent guidance on HBV from the AASLD recommending a 12-month course of peginterferon alfa for elevated HDV RNA and alanine aminotransferase levels.

The guidance authors note, however, that treatment success is low, ranging from 23% to 57%. This, coupled with a lack of specific therapies for HDV, presents a significant challenge for patients and physicians alike, according to Kwo.

“Certainly, you can give a course of interferon, but it is not particularly effective, and patients are not particularly enthusiastic about receiving longer courses of interferon,” Kwo said, highlighting some of the tolerability issues associated with peginterferon alfa. “It is the current standard of care, but it is not utilized very frequently.”

Other studies have evaluated longer durations of treatment with peginterferon alfa, including the Hep-Net International Delta Hepatitis Intervention Trial (HIDIT)-II. The results, which were published in The Lancet Infectious Diseases in 2019, showed that extending treatment with peginterferon alfa-2a to 96 weeks was possible in up to 80% of patients, with an acceptable safety profile, and led to on-treatment rates of HDV RNA suppression of approximately 40%. Nevertheless, prolonging treatment beyond the recommended 48 weeks only slightly increased HDV RNA response rates and more than one-third of responding patients experienced relapses, according to the researchers.

Perhaps more importantly, Kwo noted, treatment for such a long period of time is likely not feasible.

“Interferon works, but it can be difficult for some patients to tolerate, and on a widespread population basis, a long duration of interferon will be very problematic to administer for people, so this is not going to be practical,” Kwo said.

For patients with elevated HBV DNA levels in addition to elevated HDV RNA and ALT levels, initiating therapy with nucleotide/nucleoside analogs (NAs) is indicated. NAs, however, do not appear to be effective for HDV alone and do not increase the likelihood of an off-treatment virological response when paired with peginterferon, according to AASLD guidance.

“We need additional therapies that target different mechanisms of action for HDV as well as therapies that are better tolerated,” Kwo said. “Fortunately, we do have multiple therapies that are currently being studied, with some data suggesting that we can improve upon the efficacy rates that we’re seeing with just interferon alone.”

‘A welcome addition’

Because HDV requires HBV for replication, clearance of hepatitis B surface antigen (HBsAg) would eliminate the need for HDV treatment. However, this can be difficult to achieve, according to Kwo. Consequently, a number of new therapies are targeting HDV specifically.

One new therapy that is edging toward FDA approval is Hepcludex (bulevirtide, Gilead Sciences), an amino acid peptide that prevents HBV and HDV from entering hepatocytes by binding to and blocking the sodium taurocholate co-transporting polypeptide, HBV/HDV entry receptor according to Kwo.

Backed by promising results, the European Medicines Agency granted conditional marketing authorization to bulevirtide 2 mg in July 2020, and the treatment is currently available in the European Union. In the United States, the drug previously received breakthrough therapy designation and orphan drug status from the FDA, and the manufacturer submitted a biologics licensing application for the 2-mg dose in November 2021.

The data supporting the bid for FDA approval largely come from completed and ongoing phases 2 studies — MYR202 and MYR203 — as well as the ongoing phase 3 MYR301 study. In the phase 2 studies, bulevirtide, which is a subcutaneous injection, yielded reductions in HDV RNA levels at 24 and 48 weeks, respectively, and was generally well tolerated. In MYR203, the treatment also was studied with peginterferon alfa — a combination that led to declines in HDV RNA and HBsAg levels in a substantial number of patients, according to data presented at The Liver Meeting in 2018. Interim results from the ongoing phase 3 MYR301 study, which were presented at The Liver Meeting Digital Experience in 2021, confirmed these previous findings and linked bulevirtide monotherapy with significant decreases in HDV RNA at 48 weeks.

An increase in total bile acids was responsible for most adverse events, but this did not appear to be particularly problematic for patients, according to Kwo.

“One uncertainty about bulevirtide is that a treatment duration has not yet been defined,” Kwo said, noting that more research is still needed. “However, it appears that bulevirtide has benefit with reductions in HDV RNA and improvement in ALT levels and would be a welcome addition to our therapeutic armamentarium. Ideally, bulevirtide can be combined with other therapies in the future.”

Rise of HDV-specific therapies

Bulevirtide may be further along in its journey toward FDA approval, but several other treatments, also focused on knocking down HDV viral levels, are generating promising data.

Among these new therapies is Zokinvy (lonafarnib, Eiger Biopharmaceuticals), an oral prenylation inhibitor that blocks replication of HDV. The treatment was shown to have potential as monotherapy in a phase 2a proof-of-concept trial in 2015 and appeared even more beneficial when administered in combination with Norvir (ritonavir, AbbVie) and peginterferon alfa in the subsequent phase 2 LOWR HDV-1 and LOWR-2 studies.

“The phase 2 trial is very similar to bulevirtide and showed that you can substantially reduce the levels of HDV RNA at the end of treatment, with endpoints of undetectable HDV RNA levels or a 2-log reduction in levels,” Kwo said.

In terms of next steps, the international, multicenter, phase 3 D-LIVR study, which will evaluate two treatment regimens containing lonafarnib, also has completed enrollment and topline results are expected at the end of 2022, according to an Eiger Pharmaceuticals press release.

“Hopefully, we will be able to demonstrate improved clinical responses for HDV, and we eagerly await the data,” Kwo said.

Peginterferon lambda (Eiger Biopharmaceuticals), which is a type 3 interferon, is another therapy that is being studied alone and in combination with lonafarnib for treatment of chronic HDV, Kwo noted.

In the phase 2 LIMT trial, virologic response to peginterferon lambda for 48 weeks was comparable to that seen in historic data for peginterferon alfa, according to results presented at the International Liver Congress in 2019. Additionally, data from the phase 2 open-label LIFT study, presented at The Liver Meeting Digital Experience in 2020, showed that combining peginterferon lambda with ritonavir and lonafarnib was safe and tolerable and led to significant declines in HDV RNA levels.

Notably, an additional benefit of a type 3 interferon like peginterferon lambda, Kwo noted, is the potential for fewer adverse effects. Unlike a type 1 interferon, such as peginterferon alfa, a type 3 interferon binds to interferon receptors that are mainly expressed in the liver.

“Many of the side effects of interferon alfa are related to other receptors expressed on either the hematopoietic cells or other cells. Therefore, peginterferon lambda is better tolerated,” Kwo told Healio.

Peginterferon lambda will be further studied in the phase 3 LIMT-2 trial, which enrolled its first patient in December 2021, according to a press release.

Addressing HBV

Although these novel treatments focus more specifically on HDV viral suppression, tackling HBV infection is still an important therapeutic strategy, according to Kwo.

“Obviously, if you can knock down the HBsAg to low or undetectable levels, this will provide another opportunity to treat HDV as HBsAg levels are required for HDV replication,” Kwo said.

One such treatment, JNJ-3989 (Arrowhead Pharmaceuticals), is a small interfering RNA designed to target HBV RNA and reduce overall viral load. In the phase 2b REEF-1 study, researchers evaluated multiple combinations of JNJ-3989, JNJ-6379 and NA therapy in patients with chronic HBV. The results, which were presented in a late-breaking abstract at The Liver Meeting Digital Experience in 2021, demonstrated a dose-dependent response to JNJ-3989, with 19.1% of patients with hepatitis B receiving the highest dose plus NA achieving the primary endpoint of meeting criteria for stopping NA therapy at 48 weeks.

The injectable therapy is also being studied in patients co-infected with HBV/HDV in the REEF-D study, which is currently recruiting, according to ClinicalTrials.gov.

“This study is ongoing, and it will be interesting to see if we can, by reducing surface antigen levels, increase our treatment options for HDV,” Kwo said.

Researchers also are investigating nucleic acid polymers, which block assembly and secretion of HBV subviral particles. These therapies, including REP 2139 (Replicor) and REP 2165 (Replicor), are given in combination with peginterferon alfa and NAs to treat HBV infection. In terms of data, a nonrandomized, phase 2, open-label study published in The Lancet Gastroenterology and Hepatology in 2017 showed that a majority of 12 patients with chronic HDV achieved functional control of HBV/HDV co-infection after treatment with REP 2139 and peginterferon alfa-2a.

“This is a very interesting class of therapies,” Kwo said. “They seem to inhibit the release of HBsAg, and a preliminary study showed that there were very good responses to the combination of these nucleic acid polymers and interferon. It’s a small study, but the data are promising and hopefully we’ll see more coming forward for this class as well.”

Importance of screening

The availability of promising new therapies will undoubtedly have a meaningful impact on HDV, but physicians will only make inroads if they are able to identify patients who require treatment, according to Kwo.

“Finding and diagnosing HDV and linkage to care is actually a substantial challenge,” Kwo told Healio, noting that the true prevalence of the disease is difficult to pinpoint, because HDV tends to occur in pockets in both the U.S. and around the world.

Screening, Kwo noted, holds the key to unlocking this information. Currently, AASLD advocates a risk-based approach among patients with HBV, recommending anti-HDV screening for those who have HIV, those who inject drugs, men who have sex with men, those at risk for STDs and immigrants from areas where HDV is highly endemic. Other societies, however, including the EASL, recommend universal screening for HDV among those with HBV.

“Because the prevalence of HDV is still low compared with HCV, you have to look at cost effectiveness and other thresholds. It is the same challenge with HBV, but there are some modeling studies showing that universal screening is cost-effective for HBV. With HDV, though, the challenges may be slightly different as the disease occurs in pockets,” Kwo said. “However, I am not the only hepatologist who has occasionally been very surprised about who tests positive for HDV.”

This, Kwo noted, is one of the limitations of risk-based screening.

“While everybody understands the importance of trying to have the highest yield, the way we will find these individuals with HDV is to implement universal screening in those with HBV,” Kwo said.

“Finding these patients is important because we are now beginning to enter an era where we will actually have therapeutic options for HDV that will hopefully improve our response rates.”

References:

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• Eiger BioPharmaceuticals. Eiger BioPharmaceuticals announces complete enrollment of D-LIVR, the largest phase 3 study in hepatitis delta virus (HDV), investigating lonafarnib, the only oral agent in development for HDV. https://ir.eigerbio.com/news-releases/news-release-details/eiger-biopharmaceuticals-announces-complete-enrollment-d-livr. Published Nov. 1, 2021. Accessed Feb. 7, 2022.
• Eiger Pharmaceuticals. Eiger BioPharmaceuticals announces first patient enrolled in LIMT-2: a phase 3 study of peginterferon lambda in patients with chronic hepatitis delta virus (HDV) infection. https://ir.eigerbio.com/news-releases/news-release-details/eiger-biopharmaceuticals-announces-first-patient-enrolled-limt-2. Published Dec. 21, 2021. Accessed Feb. 7, 2022.
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