|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30441
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
Myrcludex B, a novel therapy for chronic hepatitis D?
Mario Rizzetto , Grazia Anna Niro
See Articles, pages 483–489 and 490–498
DOI: http://dx.doi.org/10.1016/j.jhep.2016.06.014 |
There is no satisfactory therapy for chronic hepatitis D (CHD). With the pegylated interferon-alpha (PegIFN) now in use, a sustained viral response is achieved in about 25% of the patients [1; however, relapses are frequent and further diminish the therapeutic efficacy [2.
Treatment efforts directed at inhibiting the replication of the hepatitis D virus (HDV) are not efficacious due to the minimalist nature of this infectious agent, which is too small to code for the proteins necessary for virus-directed synthesis; its replication relies entirely on cellular RNA polymerases redirected to duplicate the viral RNA [3. As HDV is not vulnerable to conventional antivirals, yet depends on the HBsAg coat provided by the hepatitis B virus (HBV) for the assembly of the virion [3, attention has shifted to the HBsAg as a therapeutic target for interrupting the life cycle of the HDV [2.
In this issue of the Journal of Hepatology, an HBsAg blocking strategy is presented, based on the use of myrcludex B (Myrc), a lipomyristolated peptide containing 47 amino-acids of the pre S1 domain of the HBV large surface protein. The susceptibility of the human liver to the HBsAg depends on the specific binding of the myristolated domain to the sodium taurocholate co-transporting polypeptide (NTCP) [4; targeting the NTCP with the synthetic homologous peptide competes for the binding with the natural HBsAg, and results in the restriction of virion uptake in the cell [5.
The first paper in this issue (First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B; Antje Blank et al.) assessed the safety of the drug; the concentration (IC50) of Myrc that blocks HBV and HDV entry through the NTCP is 100 times lower than that which inhibits bile acid transport. Therefore, viral block should be achieved without interfering with bile acid transport. Ascending doses of Myrc (up to 20 mg) were administered to healthy volunteers. The drug was well tolerated with no dose limiting toxicity; modest and transient elevations of amylase and lipase occurred in 7 patients but were clinically uneventful and resolved spontaneously.
The second paper (Treatment of chronic hepatitis D with the entry inhibitor myrcludex B – first results of a Phase Ib/IIa study; Pavel Bogomolov et al.) reported the interim results of the use of Myrc in CHD, and aimed to provide a proof of concept of the blocking strategy. The rationale was that the prolonged inhibition of the HDV entry by the HBsAg block should protect uninfected hepatocytes from new HDV infection, ultimately leading to the eradication of the virus.
Seven patients received Myrc in monotherapy; another 7 patients received Myrc and PegIFN, at a dose of 2 mg daily subcutaneously for 24 weeks. The 24 week results in these two Myrc cohorts were compared with the results from 7 patients given PegIFN monotherapy. The Myrc monotherapy cohort patients are to be given PegIFN alone for 48 weeks after the 24-week monotherapy is completed. The other two cohorts continue with PegIFN treatment alone for additional 24 weeks, so that all three cohorts receive 48 weeks of PegIFN treatment.
There was a consistent and uniform decline of serum HDV-RNA in each cohort, but no effect on serum HBsAg, which remained unchanged in both cohorts given Myrc. These results are paradoxical. The authors intended to reduce the spreading of HDV as a secondary effect of the HBsAg block; instead, the titre of this antigen did not change. Therefore, the primary objective of the study was not met and the proposed concept was not proven. Unexpectedly, however, Myrc alone, without an obvious interaction with the HBsAg, induced a reduction of HDV-RNA by at least one log in all treated patients and virus clearance in two patients. It also led to the normalization of alanine-aminotransferase in six patients, suggesting that the antiviral response was matched by a favourable clinical effect.
The mechanism by which Myrc may directly inhibit the expression of HDV-RNA is puzzling. Based on experimental data [[6], [7], [8]], the authors argue that Myrc could have directly reduced the number of infected cells. At present, however, this explanation remains speculative. Whatever the repressive mechanism of Myrc on HDV, the issue is whether this drug may provide an alternative therapeutic option in CHD. Interestingly, five patients given Myrc together with PegIFN, lost the HDV-RNA by week 24; this enhanced antiviral effect could suggest a synergistic effect of Myrc with the cytokine.
An increased dosage and administration period could be considered in order to achieve a more profound inhibition of HDV-RNA, as five to ten fold higher doses of Myrc were found to be safe in volunteers, compared to the 2 mg dose used in patients. However, in CHD patients, Myrc therapy was associated with a distinct elevation of the bile acids conjugated with taurine and glycine, as well as with the development of homologous antibodies in the majority. These effects were reported as uneventful but need to be further explored if therapy is to be increased.
The critical issue is whether the decline of HDV-RNA obtained with Myrc will be of long-term clinical relevance in the absence of an impact on the HBsAg. Several studies indicate that a reduction of the level of serum HBsAg is required to achieve a sustained HDV response. Baseline HBsAg levels were lower in responders than in non-responders [9, and a drop of the antigen at six months of therapy was a useful predictor of the clearance of HDV [10. In a recent study no patient reached a SVR unless serum HBsAg had declined by at least 0.105 log from baseline [11. Conversely, the persistence of unmodified HBsAg portends the risk of reactivation of hepatitis D [[12], [13]].
HDV in the HBsAg setting is highly infectious; it has been transmitted to chimpanzees carrying the HBsAg by infectious serum diluted 10−11 [14. Current assays for HDV-RNA have a sensitivity threshold of 10 copies/ml [15, and therefore a negative test does not rule out the presence of residual HDV which may cause the disease to reoccur by the persisting HBsAg state.
Though the lack of an impact on the HBsAg does not bode well for Myrc, it will be interesting to see whether inhibition of HDV-RNA is maintained or further enhanced in the second, Myrc-free part of the study, through a potentially direct effect on HDV-RNA.
|
|
发表于 2016-8-16 10:13
