Bulevirtide-PegIFNα combo yields benefits for CHD patients

A combination regimen comprising bulevirtide 10 mg (BLV10) and pegylated interferon alpha-2a (PegIFNα) improved multiple liver parameters in patients with chronic hepatitis delta (CHD), findings from the phase IIb MYR204 study have shown.

“HDV* causes the most severe form of chronic viral hepatitis, with a two- to threefold increase in mortality risk compared with hepatitis B virus mono-infection,” said Dr Tarik Asselah from the Hôpital Beaujon APHP, Clichy, Paris, France, at The Liver Meeting 2023.

“In this study of finite treatment for CHD, BLV10 combined with PegIFNα achieved the highest rates of HDV RNA undetectability, ALT** normalization, and composite response,” Asselah said.

At week 24 after end-of-treatment (EOT), there was a significantly higher proportion of patients achieving the primary endpoint of HDV RNA undetectability with PegIFNα+BLV10 than with BLV10 alone (46 percent vs 12 percent; p=0.0003). [The Liver Meeting 2023, abstract 5009]

The study evaluated 174 CHD patients (mean age 40 years, ~70 percent male) with detectable serum HDV RNA. Median HDV RNA was high (5.2–5.6 log₁₀ IU/mL). A third of participants had cirrhosis, and about half had a history of interferon use. Twenty-four patients were on PegIFNα only until week 48; 50 patients were on BLV10 alone until week 96. Fifty participants received the PegIFNα + BLV 2 mg combo (PegIFNα+BLV2) while the remaining 50 received PegIFNα+BLV10 for 48 weeks; after which, they continued BLV2 or BLV10 only until week 96.

Other outcomes

There were also marked differences between the PegIFNα+BLV10 and PegIFNα arms (46 percent vs 17 percent; p=0.0197) and the PegIFNα+BLV2 and BLV10 arms (32 percent vs 12 percent; p=0.0283).

The PegIFNα+BLV10 arm had the highest fraction of patients who had ALT normalization at week 24 after EOT (56 percent). With PegIFNα+BLV2, 42 percent were able to achieve this outcome. In the monotherapy arms, the rates were 25 percent (PegIFNα) and 30 percent (BLV10). A comparison between PegIFNα+BLV10 and BLV10 alone yielded a p-value of 0.0149.

A similar trend was observed in terms of composite response (ie, HDV RNA undetectable + ALT normalization), with PegIFNα+BLV10 trumping BLV10 alone (42 percent vs 8 percent; p=0.0001).

Rates of undetectable HDV RNA were generally higher at EOT (70, 44, 22, and 21 percent for PegIFNα+BLV10, PegIFNα+BLV2, BLV10, and PegIFNα, respectively) than the week-24-after-EOT rates (46, 32, 12, and 17 percent, respectively). According to Asselah, the drops in response rates between the two timepoints were primarily driven by relapse.

Reductions in liver stiffness were greater with any BLV-based regimen than with PegIFNα alone through week 24 after EOT (least squares mean change from baseline -2.0 vs 1.1 kPa).

HBsAg*** loss was seen with both combo regimens (8 percent [PegIFNα+BLV2] and 4 percent [PegIFNα+BLV10]), but none with monotherapy.

The rates of any grade 3/4 adverse events (AEs) tied to BLV in both combination arms were similar (4 percent for both). There were no serious AEs tied to BLV use, nor were there any treatment discontinuations owing to BLV-related AEs.

While there were dose-dependent asymptomatic elevations in bile acids across all BLV arms, these were expected due to the drug’s mechanism of action (ie, inhibition of bile acid transported NTCP^#), noted Asselah. “The increases in bile acids occurred early and mean levels were stable with continued treatment. These were also reversible upon treatment completion.”

Addresses a treatment gap

Though recommended off-label for CHD, PegIFNα is tied to low rates of sustained undetectable HDV RNA post-therapy and high relapse rates. [Liver International 2022;00:1-11] BLV2, a first-in-class entry inhibitor, has been approved in the EU for the treatment of CHD and compensated liver disease in adults.

The current study demonstrated the superiority of the PegIFNα+BLV10 combo regimen to monotherapy with either agent, noted Asselah. BLV2 also showed favourable signals when combined with PegIFNα. The improvements in liver stiffness were consistent across all BLV-based regimens, and HBsAg loss was infrequent.

“[Taken together, our] study addresses a major treatment gap for HDV, a finite treatment regimen that results in sustained off-treatment viral response,” Asselah said.

“Assessment of the durability of undetectable HDV RNA at 48 weeks after EOT is planned … Longer-term off-treatment data will help define the durability of finite therapy with BLV in combination with PegIFNα for CHD,” he added.