Eiger's HDV Program Sees Cirrhosis in Younger Patients (Updated)

Liver Disease_Compressed

Commercial-stage biopharma company Eiger Biopharmaceuticals released interim data from its ongoing Phase III D-LIVR trial, showing that cirrhosis is alarmingly common among patients with chronic hepatitis D virus (HDV) infections, even in those who are relatively young. The company also presented data from its Phase II study of peginterferon lambda, which is being developed to treat the disease. It is also being studied in combination with another asset, lonafarnib. 

The first abstract, presented during a poster session at the European Association for the Study of the Liver's (EASL) 2022 International Liver Congress, revealed that of the 407 D-LIVR participants, nearly 30% developed liver cirrhosis. Among those who progressed to cirrhosis, 40% were 45 years of age or under. Results also suggested that subtle perturbations in platelet count and the international normalized ratio could be early signals of cirrhosis in relatively young patients.

Known as the most severe form of human viral hepatitis, HDV can only occur as a co-infection with the hepatitis B virus. Worldwide, HDV afflicts some 15 to 20 million people and can lead to liver cancer and liver failure. Approximately six in 10 HDV patients die within ten years. HDV can also progress to cirrhosis, which develops when the liver becomes scarred and permanently damaged.

Aside from HDV, cirrhosis can also arise from infections, other liver diseases and drinking problems. In recent years, researchers have flagged a worrying rise in the incidence of cirrhosis among younger people, not unlike the trend that emerged in D-LIVR. In 2020, for example, a study published in the Journal of the American Medical Association Network Open found that hospitalizations for alcoholic cirrhosis in the United States grew from 2012 to 2016, costing the country more than $20 billion. Viral hepatitis accounted for around a third of all liver disease-related hospitalizations.

Lonafarnib is a first-in-class oral prenylation inhibitor that treats chronic HDV by preventing the virus from assembling its individual components. Currently, the drug candidate is the only oral treatment for HDV in development. Eiger gained the exclusive worldwide rights to lonafarnib under a licensing agreement with pharma giant Merck.

Seeking to evaluate Lonafarnib-containing drug regimens, D-LIVR is a global, multi-center, Phase III study that is shaping up to be the world's largest cohort for HDV to date. The trial's primary objective is to show that, after 48 weeks of treatment, lonafarnib can induce a ≥2-log decline in HDV RNA levels while also achieving normal levels of the liver enzyme alanine aminotransferase.

Lonafarnib continued to make waves elsewhere at EASL. In a separate poster presentation, the drug showed strong activity against HDV when combined with peginterferon lambda. The combo achieved a higher success rate, defined as a 2-log or greater drop in HDV RNA, compared with lambda treatment alone. There were also no null responders in the treatment arm receiving the drug combo. 

Results also pointed to a notable reduction in the triphasic kinetic patterns, suggesting that adding lonafarnib to treatment regimens might indeed interfere with the production and release of HDV RNA.

"Eiger’s motivation behind the development of lonafarnib and peginterferon lambda is to register first-in-class therapies with different mechanisms targeting HDV with a goal of making options available to patients," Eiger SVP Clinical Development Ingrid Choong, Ph.D. told BioSpace via e-mail. 

She explained the mechanism of action behind both drugs. 

"Both lonafarnib and peginterferon target critical host processes involved in viral replication. Lonafarnib is a prenylation inhibitor that blocks host farnesyl transferase. Inhibiting prenylation of the large delta antigen during HDV replication blocks the ability of HDV to steal HBV surface antigen (HBsAg), which is necessary to complete the HDV virus assembly," Choong said, addiing that "...with HCV and HIV viruses, it is believed that combinations with different mechanisms of action may deliver the most benefit to HDV patients."

Week 48 data from the D-LIVR trial is expected by the end of this year. Meanwhile, a Phase III LIMT-2 study of peginterferon lambda is in the midst of enrolling patients and activating sites. 

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