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First hepatitis D medicine is given restricted approval in Scotland after US rejection

BMJ 2023; 380 doi: (Published 20 March 2023) Cite this as: BMJ 2023;380:p660
  1. Elisabeth Mahase
  1. The BMJ

Scotland has become the first country in the UK to approve a specific treatment for the hepatitis delta virus (HDV), after it granted bulevirtide (Hepcludex) “restricted use” approval for patients with chronic infection and compensated liver disease.1

The drug (2 mg powder for injection) will be made available for patients with evidence of significant fibrosis who have not responded to or cannot take interferon based treatment.

Hepatitis D is found only in people with chronic hepatitis B and infects about 5% of such patients. It is considered the most severe form of chronic viral hepatitis and is known to progress rapidly towards liver cancer and liver related death.2

The approval by the Scottish Medicines Consortium comes after the drug was rejected by the US Food and Drug Administration last year. Its manufacturer, Gilead, said that the US agency had raised “concerns regarding the manufacture and delivery” but did not request any new studies to evaluate the safety and efficacy of bulevirtide.3 The FDA did not provide The BMJ with any further details on its concerns. The US has no other approved treatments for HDV.

In England and Wales the National Institute for Health and Care Excellence is still assessing bulevirtide, and a final decision is expected on 31 May 2023,4 although draft guidance released last November did not recommend the drug because of uncertainties around its clinical and cost effectiveness.5

Bulevirtide has been made available in some other countries, having received conditional marketing authorisation in the EU in 2020. However, as part of that approval agreement Gilead is required to complete a phase 3 clinical trial assessing the efficacy of the treatment, with results due in February 2025.6

Surrogate endpoints

The Scottish Medicines Consortium’s approval is based on preliminary data from the ongoing phase 3 trial, which uses surrogate virological and biochemical outcomes that are believed, although not proved, to confer clinical benefit.

The approval document said that bulevirtide was “superior” to delayed treatment (observation until week 48 then bulevirtide to week 144), with a 43% improvement in the primary outcome at week 48. The primary outcome was undetectable HDV RNA or a decrease in HDV RNA by ≥2 log10 IU/mL from baseline and alanine aminotransferase (ALT) normalisation.

The document explained, “Elevated ALT is suggestive of ongoing necro-inflammation of the liver and ALT normalisation has been associated with a decrease in the rate of progression of fibrosis to cirrhosis in hepatitis B and C and is considered relevant for hepatitis D.”1

However, data on disease progression to clinically important events, such as cirrhosis and liver transplant, as well as clarity on the optimal treatment course, are not yet available. These details are expected to come from the ongoing phase 3 study.

Adverse events by week 48 were reported by 82% (40/49) in the bulevirtide 2 mg group and 76% (39/51) in the delayed treatment group. In the bulevirtide group 4.1% reported a serious event, which compares with 2% in the delayed group.

No patients in either group discontinued treatment because of an adverse event, but the approval document did note an observed increase in bile salts with bulevirtide, as noted in the patient leaflet.

Responding to the approval, Véronique Walsh, Gilead Sciences’ UK & Ireland vice president and general manager, said, “For years, chronic hepatitis delta virus infection has proven to be a notoriously difficult challenge to treat, with no licensed therapy options in the UK. [This] recommendation is a vitally important turning point, providing the option of bulevirtide across the NHS in Scotland.”


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