Hepatitis B Foundation Drug Watch 显示REP 2165 & REP 2139都处于Phase 2阶段。我查了以下好像处于phase 2阶段有几年了。
这个是不是可以期待阿。作者: newchinabok 时间: 2018-8-23 16:51
东海以东 发表于 2018-8-23 16:00
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Hepatitis B Foundation Drug Watch 显示REP 2165 & REP 2139都处于Phase 2阶段 ...
绝对可以期待作者: windu 时间: 2018-8-23 18:44
可以不断期待…作者: newchinabok 时间: 2018-8-23 19:44
本帖最后由 newchinabok 于 2018-8-23 20:01 编辑
windu 发表于 2018-8-23 18:44
可以不断期待…
我的心,在等待,在呀,在等待呀。作者: StephenW 时间: 2018-8-23 20:55
Combination HBV Therapy Shows Functional Control 24 Weeks After Cessation
Healio Gastroenterology, August 2018
Replicor recently shared follow-up data from the ongoing REP 401 trial that showed high rates of persistent functional control of hepatitis B after cessation of therapy with REP 2139-Mg or REP 2165-Mg plus pegylated interferon alpha-2a and tenofovir disoproxil fumarate, according to a press release.
“REP 2139’s ability to rapidly reduce [HBV surface antigen] in 90% of patients is unique in the industry and is accompanied by immediate reductions of viremia in the blood and viral replication in the liver,” Andrew Vaillant, PhD, chief scientific officer at Replicor, said in the release. “In preclinical studies, this effect alone has led to complete control of and profound reduction of cccDNA in the liver.”
Among patients who completed 24 weeks of treatment-free follow-up, 87% had functional repression with 79% showing HBsAg levels less than 10 IU/mL, 70% had functional remission with 66% showing no detectable HBsAg, and 92% had normal liver function.
The researchers reported the combination therapy to be well-tolerated. PEG-IFN treatment resulted in mild side-effects but presented significant reactivation of HBV immune response and increased anti-HBs, the appearance of therapeutic transaminase flares and the establishment of functional control.
“The tolerability of PEG-IFN in the REP 401 trial was substantially better than when used with ribavirin in HCV infection,” Vaillant said in the release. “Although other immunotherapies will be assessed in future combination settings, the inclusion of PEG-IFN in REP 2139-Mg based combination therapy represents an option with clear clinical activity and benefit that can give patients access to the first effective finite therapy for HBV and HDV infection.”
NAPs are phosphorothioated oligonucleotides (PS-ONs) whose antiviral effect against HBV infection is independent of nucleotide sequence [11, 12]. Unlike standard antisense compounds, NAPs can be more easily engineered to remove the secondary pro-inflammatory / immunostimulatory effects of single stranded nucleic acids while maintaining their antiviral activity in vivo [13, 15]. The primary tolerability issue with REP 2055 in the REP 101 study was IV administration related side effects similar to those reported for other PS-ONs administered to humans by IV infusion [16, 17] which was well controlled with REP 2139-Ca in the REP 102 study. Additionally, short term combination therapy with REP 2139-Ca and thymosin or peg-IFN up to 26 weeks was well tolerated. The liver flares during monotherapy with either REP 2055 or REP 2139-Ca occurred following initial reductions of serum HBsAg and HBV DNA, were self-resolving with continued NAP therapy and were not accompanied by any symptoms or serological evidence of liver dysfunction. These liver flares are also routinely observed with treatment with interferons, and are thought to be evidence of re-activation of immune function in the liver [18]. These liver flares may be evidence of reactivation of the immune response in the liver with reduction of circulating HBsAg (discussed below) but additional analysis of T-cell response during transaminase flares concomitant with serum HBsAg reduction in future trials will be required to address this hypothesis.
PS-ONs increase mineral elimination in the urine [19] and the resulting compensatory response includes liberation of mineral stores (along with heavy metals if present) from the bones into the circulation. All study patients and untreated control subjects at the trial site were shown to have substantial pre-existing heavy metal loads (data not shown) as a result of chronic heavy metal exposure known to be endemic at the trial site [20–22]. The 2’ ribose modifications present in REP 2139 are absent in REP 2055 (Fig 2) and serve to reduce immunoreactivity [23, 24] but also block degradation by endonucleases [25], rendering REP 2139 substantially more stable than REP 2055 and leading to greater accumulation of REP 2139-Ca in pre-clinical models with chronic exposure (A. Vaillant, unpublished data). Thus chronic exposure to REP 2139-Ca likely establishes a greater mineral elimination (and heavy metal liberation) than REP 2055, consistent with development of hair loss, dysphagia and dysgeusia observed in patients with REP 2139-Ca therapy but not with REP 2055.
These symptoms have not been previously reported with the clinical use of PS-ONs, however, these studies are the first to be conducted in a locale where substantial heavy metal exposure is highly endemic in the population. Importantly, in a currently ongoing clinical trial with REP 2139-Ca in Caucasian patients (REP 301 study, NCT02233075) in a European locale where patients with heavy metal exposure were excluded from participation, none of these symptoms have been observed with comparable REP 2139-Ca exposure in combination with peg-IFN (A. Vaillant, unpublished data).
These clinical observations underscore the importance of being aware of the potential complications of the enhanced mineral elimination known to occur with PS-ON therapy in general and further suggest that mineral supplementation should accompany any oligonucleotide based therapy, regardless of the disease state in patients receiving therapy.