*3.5. REP-2139*

REP-2139 is a nucleic acid polymer (NAP), which acts as a secretion inhibitor. The currently available studies investigated its role as monotherapy and in combination with NA or IFNa for 24–48 weeks, either IV or SC [16,41]. The suggested role of this compound is the removal of HBsAg from the blood, unmasking the anti-HBs response, and finally allowing the HBV clearance. Moreover, leading to a favorable immunological activation in the absence of HBsAg, this drug would potentially enhance the effect of IFNa and TDF [16,41]. Even considering all chance-related uncertainties, and due to the lack of pharmacokinetic data on REP-2139, its relative resemblance to other compounds under current use for different conditions, such as mipomersen for homozygous familial hypercholesterolemia, might lead us to consider similarities in terms of absorption, distribution, metabolism and elimination. Hence, it showed a dose-dependent maximum plasma concentration at the end of a 2-h IV infusion or SC administration, while the time of peak concentrations (t max) were typically observed 3–4 h after SC dosing and the half-time was quite long, with post-distribution-phase plasma concentrations well predicting tissue concentrations and pharmacological activity [16]. Regarding REP-2139, some data on safety are currently available. Administration-related side effects, including fever and chills, were commonly experienced but generally did not require specific therapy. As in all oligonucleotides, an improved tolerability was then attributed to the neutralization of the chelation of calcium or magnesium. Importantly, significant elevation flares of ALT and AST (>10X ULN) were frequently observed during REP-2139-Ca monotherapy in HBV/HDV patients, treated either with monotherapy or combination therapy [42]. This phenomenon, though, was self-limited and so did not require any dose adjustment and/or interruption of treatment (Table 1).

**Table 1.** Summary of pharmacology and safety of current and investigational therapies of hepatitis B and D.

