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Specialty Pharmacy Continuum • November/December 2021
CLINICAL
Hepatitis D Pipeline Looks Promising Interim results from a new phase 3 trial support the safety and efficacy of monotherapy with bulevirtide (Hepcludex, Gilead) in patients who have chronic infection with the hepatitis delta virus (HDV). Coupled with recent data on oral HDV regimens, the pipeline for treating this rare, challenging form of hepatitis looks promising. The interim phase 3 study, an international, multicenter investigation, concluded that treatment with bulevirtide for 24 weeks was associated with significant decreases in viral RNA and improvements in biochemical disease activity. The researchers said the findings confirm the August 2020 conditional approval by the European Commission of bulevirtide. The first-in-class entry inhibitor has received a breakthrough therapy designation from the FDA in the United States. Bulevirtide is a peptide derived from the hepatitis B surface antigen (HBsAg). “In previous phase 2 trials [MYR202/ MYR203], we showed that if you inject hepatitis D patients with this peptide [daily] with different doses, you get a linear decline in HDV RNA over time, which reflects a loss of infected cells,” said Heiner Wedemeyer, MD, the chair of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical Hospital, in Germany. The current study was a 24-week analysis of the MYR301 trial, which comprised 150 patients (57% men; mean age, 41.8 years) coinfected with hepatitis B virus (HBV) and HDV. Participants in the trial were randomized to one of three groups: no antiviral treatment for 48 weeks followed by 10 mg daily of bulevirtide for 96 weeks (control arm A; n=51), 2 mg daily of bulevirtide (arm B; n=49), or 10 mg daily of bulevirtide (arm C; n=50). Patients in arms B and C received the drug for 144 weeks, with a treatmentfree follow-up of 96 weeks. The primary end point of the trial was a combined response of undetectable HDV RNA or HDV RNA reduction of at least 210 IU/mL and normalization of alanine aminotransferase (ALT) at week 48. Secondary end points included undetectable HDV RNA, a fall in HDV RNA of at least 210 IU/mL, normalization of ALT and a reduction in HBsAg of at least 110 IU/mL. In a presentation at the 2021 International Liver Congress (abstract LBP-2730), Dr. Wedemeyer reported that after 24 weeks, none of the patients in the control group (arm A) achieved a combined virologic and biochemical response, whereas 36.7% of patients in arm B and 28.0% of those in arm C did so
(P<0.0001). Similar results were observed for HDV RNA, which fell by at least 210 IU/mL between baseline and week 24 in 3.8% of patients in arm A, 55.1% in arm B and 68% in arm C (P<0.0001). At week 24, normalization of ALT was achieved by 53.1% of patients in arm B and 38% in arm C, compared with 5.9% in arm A (P<0.0001). The level of HBsAg did not show relevant declines in all but one patient at week 24. “The important message is that the findings of the phase 2 trials were exactly confirmed,” Dr. Wedemeyer said. Safety analyses found that treatmentrelated adverse events were much more common in patients who received the study drug. “As was expected, bile acids
increased because bulevirtide’s mode of action blocks a bile salt transporter,” Dr. Wedemeyer said. “But there were no unexpected serious adverse events.” The researchers acknowledged that only a small proportion of patients had completely undetectable HDV RNA, but they were encouraged by the results. “This confirms that we can use the drug in a real-world setting,” Dr. Wedemeyer said. “These are exciting times for hepatitis delta patients.” Tobias Böttler, MD, an attending physician at the University Hospital Freiburg, in Germany, commented that bulevirtide has the potential to make a significant difference in managing patients with active hepatitis delta infection. “We still need to learn a lot with regard to dosing, treatment duration and possible combination therapies, [because] some data suggest that combination with interferon is even more potent,” he said. “It appears to be well tolerated with little side effects, based on the data we currently have. Going forward, we might ht even
Hepatitis D: FAQs Q: What are some of the key distinguishing features off the h h hepatitis i i D virus (HDV) and its associated illness? A: HDV is known as a “satellite virus,” because it can only infect people who are also infected by the hepatitis B virus (HBV). HDV infection can be acute or lead to chronic, long-term illness. The infection can be acquired either simultaneously with HBV as a coinfection, or as a superinfection in people who are already chronically infected with HBV.
Q: What is the difference between HBV/HDV coinfection and HDV superinfection? A: HBV/HDV coinfection occurs when a person simultaneously becomes infected with both HBV and HDV, whereas HDV superinfection occurs when a person who is already chronically infected with HBV acquires HDV. Although acute HBV/HDV coinfections can resolve, HDV superinfection can lead to rapid progression of the already present HBV infection, resulting in liver cirrhosis and liver failure. These outcomes occur within five to 10 years in 70% to 80% of affected people and within one to two years in 15% with chronic HBV/HDV infection.
Q: How common is hepatitis D in the United States? A: HDV infection is uncommon in the United States; most U.S. cases occur among people who migrate or travel here from countries where HDV is endemic. Because hepatitis D is not a nationally notifiable condition, the actual number of hepatitis D cases in the United States is unknown.
Q: Where is hepatitis D most common? A: Hepatitis D is most common in Eastern Europe, Southern Europe, the Mediterranean region, the Middle East, West and Central Africa, East Asia, and the Amazon Basin in South America.
be able to use the drug in hepatitis B– monoinfected patients, but that requires a lot more data from clinical trials.”
Oral Formulation Option For patients and providers who prefer orally administered therapy, another investigational agent, lonafarnib (Zokinvy, Eiger Biopharmaceuticals), may be an option if it succeeds in its pipeline journey. Lonafarnib is a late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in the modification of proteins through a process called prenylation. The FDA approved the drug in 2020, to reduce the risk for death from Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in patients 1 year of age and older. Lonafarnib has been evaluated in several clinical trials for the treatment of HDV, either as monotherapy or in combination with pegylated interferon alfa-2a (PEG IFN-alfa-2a) or ritonavir. In a proof-ofconcept study that explored optimal treatment regimens, the addition of ritonavir to ti a twice-daily oral lonafarnib regimen of lo 100 mg yielded optimal antiviral responses, with sigantivira nificantly fewer gastrointestieffects than lonafarnib nal side ef monotherapy (Hepatology monothe 2018;67[4]:1224-1236).The 2018;67[ GI side effects likely reduced G are due to ritonavir’s ability to inhibit lonafarnib metabolism, allowing for higher concentrations of the farnesyl transferase inhibitor to build up in the liver and systemic circulation, the researchers noted. In 2018, the FDA granted lonafarnib breakthrough therapy designation for the treatment of HDV infection. The drug currently is being investigated in D-LIVR, a global phase 3 trial evaluating an all-oral arm of lonafarnib boosted with ritonavir. The trial also includes a combination arm of ritonavir boosted with ritonavir plus PEG IFN-alfa-2a. Each arm is to be compared with a placebo arm in HDV-infected patients (ClinicalTrials.gov identifier: NCT03719313). The estimated study completion date is April 1, 2023, according to the ClinicalTrials. gov listing. —Michael Vlessides, David Bronstein
Q: Are there different genotypes of HDV, and where do they circulate? A: Eight different HDV genotypes can be found around the world, all of which share the same transmission routes and risk groups. HDV genotype 1 circulates mainly in North America, Europe, the Middle East, and North Africa. Genotypes 2 and 4 can be found in East Asia. Genotype 3 is found exclusively in the Amazon Basin in South America. Genotypes 5, 6, 7 and 8 are found in West and Central Africa. Source: CDC (bit.ly/3jOmrI2).
Dr. Böttler reported that he served on an advisory committee for Gilead Sciences. Dr. Wedemeyer reported financial relationships with Abbott, AbbVie, Altimmune, Biotest, Bristol Myers Squibb, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens and Transgene.
