早期研究在慢性HBV Tx中取得進展 —研究人員被證明是安全，

StephenW

Early Studies Make Headway in Chronic HBV Tx
— Investigational agents prove safe, tolerable

by Ed Susman, Contributing Writer, MedPage Today August 29, 2020

This article is a collaboration between MedPage Today and:

Researchers reported promising results in several early-stage studies of hepatitis B virus (HBV) treatments at the digital Internal Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL),

In a phase II study of selgantolimod, given to patients who had already been able to suppress the virus, the oral agent appeared to allow for a deep drop in circulating virus, according to Edward Gane, MCChB, MD, of the University of Auckland.

In two of 48 patients total, the key HBV surface antigen (HBsAg) disappeared, he added.

Gane also reported that three patients post-treatment no longer had HBV antigen (HBeAg), a signature protein that indicates the virus is transmittable.

The antigen decline of more than 1log10 occurred in 30% of the patients on selgantolimod at 24 weeks and was sustained at 48 weeks.

"Common treatment-emergent adverse events [TEAE] were generally gastrointestinal-related, and most cases were mild and transient," he said. "Further evaluation of selgantolimod in combination studies with complementary immune and antiviral targets is planned."

The primary endpoints of the study – in which patients were given one of two doses of selgantolimod – were safety and tolerability of the investigative agent and the percentage of patients who were able to reduce HBsAg at least 1log10 from baseline at week 24. The study continued for 48 weeks with treatment stopped after 24 weeks. Ten patients got a 1.5-mg dose of the agent, while another 10 received 3 mg, and 19 got placebo.

A second study showed that the investigational agent GSK'836 has the potential to suppress HBV after 4 weeks of treatment in patients with chronic HBV.

The antisense oligonucleotide led to reductions in HBsAg and HBV DNA versus placebo after 4 weeks of treatment in people with chronic HBV on stable nucleoside or nucleotide analogue (NA) therapy, and in patients who were NA-naïve, reported Man-Fung Yuen, MBBS, MD, of Queen Mary Hospital/University of Hong Kong.

The agent was administered subcutaneously at a dose of 300 mg on days 1, 4, 8, 11, 15, and 22 in 31 patients.

Even though the numbers of patients in the phase IIa trial were small, there was a significant difference in reduction of HBsAg when compared with placebo at day 29, Yuen stated. Among patients not on NA therapy, there was a mean 1.566log10 drop versus decrease with placebo (P<0.0001).

In those patients on NA therapy, there was a 2.514log10 decline versus 0.008log10 drop with placebo, although the finding was not statistically significant because of the small patient population, Yuen pointed out.

One patient developed a fever and discontinued the study. Other TEAE were injection site pain and transient asymptomatic liver enzyme elevations.

"The development of novel therapeutics for persistent HBV infection is currently one of the most vibrant fields in hepatology," commented Tobias Böttler, MD, of the University Hospital Freiburg, Germany, in a statement.

Böttler, a member of the EASL governing board, noted that "With so many different approaches that show promising results regarding HBsAg-decline, and even HBsAg-loss, we appear to be edging closer to the development of a functional cure."

Other noteworthy studies were:

    In a 40-patient study, 39 recorded an HBsAg nadir of more than 1log10 with the combined treatment of NA therapy and the RNA-interference agent JNJ-3989. The reductions were sustained for at least 9 months.
    In an ongoing study, 24 patients with chronic HBV received the RNA-interference agent VIR-2218 along with NA therapy. A subset of patients who received the 50-mg dose achieved maximal reductions in HBsAg at week 12, with a mean reduction of 1.5 log10 from baseline. A mean reduction from baseline in HBsAg of 1.0log10 was maintained through week 28 in this cohort.
    In a phase I study, 59 patients with chronic HBV on NA therapy received subcutaneous RO7062931 over 4 weeks. Dose-dependent reductions in HBsAg were observed, and the largest mean nadir HBsAg reductions of 0.5 log10 were observed with the 3 mg/kg weekly dosing regimen.

Disclosures

Gane disclosed relevant relationships with AbbVie, ALIGOS, Assembly Biosciences, Gilead Sciences, Janssen, Roche, VIR Bio, and Mylan.

Yuen disclosed relevant relationships with AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myers Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, and Spring Bank Pharmaceuticals.

Böttler disclosed no relevant relationships with industry.

StephenW

早期研究在慢性HBV Tx中取得進展
—研究人員被證明是安全，可以忍受的

作者：MedPage今日撰稿人Ed Susman 2020年8月29日

本文是MedPage Today與以下人員之間的合作：

研究人員在歐洲內部肝臟研究協會（EASL）的年度會議“數字內部肝臟大會”上報告了幾項乙型肝炎病毒（HBV）治療早期研究的令人鼓舞的結果，

奧克蘭大學MCChB，MD的愛德華·甘恩說，在針對已經能夠抑制該病毒的患者進行的塞崙戈莫德的II期研究中，口服製劑似乎可以使循環病毒深度下降。

他補充說，在總共48例患者中有2例中，關鍵的HBV表面抗原（HBsAg）消失了。

蓋恩還報告說，三名治療後的患者不再具有HBV抗原（HBeAg），這是一種標誌蛋白，表明該病毒可傳播。

在24週時，使用舍格莫德治療的患者中有30％的患者出現了超過1log10的抗原下降，並持續48週。

他說：“常見的突發治療不良事件（TEAE）通常與胃腸道有關，大多數情況是輕度和短暫的。” “計劃在具有互補的免疫和抗病毒靶標的組合研究中進一步評估selgantolimod。”

該研究的主要終點（即給患者服用兩種劑量的selgantolimod中的一種）是研究藥物的安全性和耐受性，以及能夠在第24週時從基線降低HBsAg至少比基線低1log10的患者百分比。研究繼續持續48週，治療24週後停止。 10名患者服用了1.5毫克的藥劑，另外10名服用了3毫克的藥劑，還有19名服用了安慰劑。

第二項研究表明，研究藥物GSK'836有潛力在慢性HBV患者治療4週後抑制HBV。

MBBS的Man-Fung Yuen報導，在穩定的核苷或核苷酸類似物（NA）治療的慢性HBV患者中，以及在NA初次接受治療的慢性HBV患者中，與安慰劑相比，反義寡核苷酸導致HBsAg和HBV DNA相對於安慰劑減少。香港大學瑪麗醫院醫學博士。

在31位患者的第1、4、8、11、15和22天，以300 mg的劑量皮下給藥。

Yuen指出，儘管IIa期試驗的患者人數很少，但與安慰劑相比，在第29天時HBsAg的降低仍存在顯著差異。在未接受NA治療的患者中，平均下降1.566log10，而安慰劑下降（P <0.0001）。

Yuen指出，在那些接受NA療法的患者中，安慰劑組下降了2.514log10，而安慰劑組下降了0.008log10，但由於患者人數少，這一發現在統計學上並不顯著。

一名患者發燒併中止了研究。其他TEAE是注射部位疼痛和短暫性無症狀肝酶升高。

德國弗賴堡大學醫院的TobiasBöttler醫師評論說：“開髮用於持續性HBV感染的新療法是目前肝病領域中最活躍的領域之一。”

EASL理事會成員Böttler指出：“採用許多不同的方法在HBsAg下降甚至HBsAg損失方面顯示出令人鼓舞的結果，我們似乎正在接近功能性治療的發展。”

其他值得注意的研究是：

    在一項有40位患者的研究中，有39位患者聯合應用NA療法和RNA干擾劑JNJ-3989記錄了HBsAg最低點超過1log10。減少持續至少9個月。
    在一項正在進行的研究中，有24例慢性HBV患者接受了RNA干擾劑VIR-2218以及NA療法。接受50 mg劑量的一部分患者在第12周達到HBsAg的最大降低，與基線相比平均降低1.5 log10。在該隊列中，直到第28週，HBsAg相對於基線的平均減少量為1.0log10。
    在一項I期研究中，接受NA治療的59例慢性HBV患者在4週內接受了皮下RO7062931。觀察到劑量依賴性的HBsAg降低，每週3 mg / kg的給藥方案觀察到最大平均最低谷HBsAg降低0.5 log10。

披露事項

蓋恩（Gane）透露了與AbbVie，ALIGOS，Assembly Biosciences，Gilead Sciences，Janssen，Roche，VIR Bio和Mylan的相關關係。

Yuen透露了與AbbVie，Arbutus Biopharma，Assembly Biosciences，Bristol Myers Squibb，Clear B Therapeutics，Dicerna Pharmaceuticals，Gilead Sciences，GlaxoSmithKline，Janssen，Merck Sharp和Dohme和Spring Bank Pharmaceuticals的相關關係。

Böttler透露與行業沒有任何關係。