Consensus reached on design of clinical trials for novel, curative HBV therapies
medwireNews: A panel of hepatitis B virus (HBV) experts has issued a consensus statement intended to aid in standardizing the efficacy and safety appraisals of novel, potentially curative antiviral and immune modulatory agents.
The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver organized a workshop at which these issues were discussed by key stakeholders, including academics and representatives of regulatory bodies and biopharmaceutical companies. A third of the 202 participants completed a survey prior to the workshop and the topics were also subsequently discussed in a closed session involving 23 experts.
One of the key issues on which consensus was reached was the definition of a cure. The majority of involved parties agreed that a “complete sterilizing cure,” characterized by undetectable levels of hepatitis B surface antigen (HBsAg) and complete eradication of HBV DNA, was unlikely with the antiviral and immune modulatory agents currently under development. Therefore, a “functional cure,” defined as the sustained loss of HBsAg with or without development of hepatitis B surface antibodies, was endorsed as a feasible goal.
Achieving undetectable levels of HBV DNA and HBsAg loss were agreed upon as the key primary efficacy endpoints for phase II and III trials, respectively. Six months post-treatment was considered the ideal timepoint for assessing the primary endpoint in phase III trials by the majority (65%) of the stakeholders, with longer term follow-up essential, but consensus was not reached regarding the optimal assessment timepoint for phase II trials.
The panel agreed that combination treatment with antivirals and immune modulatory drugs will likely be needed to achieve HBV cure but the members recommend that the safety and efficacy of new agents be tested initially in monotherapy trials before progressing to assessments of combination regimens.
Consensus was also reached regarding the need for development of standardized assays for assessing efficacy or predicting response in parallel with the drug development pathway; ideally, the new treatments and assays should gain regulatory approval simultaneously, the panel noted.
Finally, the stakeholders stressed that the safety of any novel curative therapies must undergo stringent evaluation, given the “remarkable safety profile” of currently available nucleos(t)ide analogs. There was no consensus on when a trial should be terminated due to safety concerns, but the involved parties suggested that “any death or liver transplantation, hepatic decompensation, irreversible autoimmunity, or incidence of severe hepatitis flare in >5% of patients could prompt a halt.”
Anna Lok, from the University of Michigan in Ann Arbor, USA, and fellow authors of the published statement say that “[c]ooperation between academia, industry, and regulatory agencies to standardize and validate surrogate markers for cure, in order to facilitate the development of curative therapies and to facilitate the path from discovery to regulatory approval, is required.”
And they conclude: “Continued collaboration among the stakeholders will make HBV ‘cure’ a reality for patients with chronic HBV.”
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