2011년 6월 임상 시험 단계에 있는 최신 B형 간염 치료제들

[다야]

Hepatitis B drugs in development

Lei Chou

Introduction (소개)

After a burst of hepatitis B virus (HBV) drug discovery and development over the last decade, the year 2010 saw the development pipeline dry up. While several currently available drugs are highly effective at controlling viral replication and keeping the disease in check, only about one-third of people are able to reach a key treatment goal: sustained viral control while safely off treatment. Life-long suppressive therapy with antiviral drugs appears to be the HBV treatment model for the near future for most people with chronic hepatitis B.

폭발적인 B형 간염 바이러스 약이 최근 10년동안에  발견되고 개발된 후, 2010년은 개발 파이프라인이 마른 것으로 보았다. 현재 몇몇 이용할 수 있는 약들이 바이러스 복제를 조절하고 검사로 질병을 유지하는데 많은 효과가 있지만, 단지 대략 사람들의 3분의 1만이 기본적인 치료 목표에 도달할 수 있다.: 지속적인 바이러스를 제어하지만 안전한 치료는 아니다. 항바이러스 약들로 장기간 억제하는 치료법은 만성 B형 간염을 가진 대부분의 사람들을 위한 가까운 미래를 위한 HBV 치료 모델인거 같다.

Although antiviral drugs can control HBV, drug resistance may develop over time, leaving people with no treatment options. This is of particular concern as resistance can develop faster for people coinfected with HIV and HBV. Long-term toxicity is likely to be an issue. These concerns will not be resolved until there is a robust drug pipeline. Advances in basic science are needed to better understand HBV pathogenesis, identify new drug targets, and to stop HBV’s destructive track.

비록 항바이러스 약들이 HBV를 제어할 수 있지만, 약의 내성은 시간이 지날수록 늘어날 수 있고, 치료 선택이 없도록 내버려둔다. 내성과의 특별한 관계는 HIV와 HBV에 동시 감염된 사람들에게는 더욱 빨리 악화될 수 있다. 이런 걱정들은 강력한 약 파이프라인이 있을 때까지는 해결되지 못할 것이다. 기초과학의 진보가 HBV 발병을 더욱  이해하고, 신약 타깃을 확인하고, HBV의 파괴적인 궤도를 정지시키는 것이 필요하다.

While overall cancer rates are on the decline nationally, liver cancer is bucking this trend, driven primarily by chronic viral hepatitis. A recent Centers for Disease Control and Prevention (CDC) publication reported that liver cancer is on the rise: between 2001 and 2006, the incidence of liver cancer increased at an annual rate of 3.5 percent, representing over 45,000 reported cases in the same period. Asians, Pacific Islanders, and African Americans have the highest rates of increase (CDC 2010).

전반적인 암 비율은 국제적으로 감소하고 있지만, 만성 바이러스성 간염에 의해 주로 내몰리는  간암은 이런 경향에 반대되고 있다. 한 최근 CDC 센터 발표는 간암이 증가하고 있다: 2001 ~ 2006년, 간암 발생은 같은 기간의 경우에 보고되었던 45,000이 넘게 나타나는 연간 3.5 퍼센트씩 증가했다. 아시아인, 태평양 섬사람과  아프리카 대륙 미국인은 가장 높은 증가비율을 가지고 있다.

HBV treatment can prevent the development of life-threatening complications, such as cirrhosis and liver cancer. But in the U.S., an estimated 5.3 million people with chronic viral hepatitis (hepatitis B and C) are over 50% percent of the undiagnosed. The challenge is to screen, diagnose, monitor, and treat people in a timely matter, before they develop serious complications. HBV treatment may prevent these complications, not treat them. Sadly, U.S. federal investment in research, testing, surveillance, and publicly funded treatment programs is grossly inadequate at present.

HBV 치료는 삶을 위협하는 간경변, 간암과 같은 문제들을 막을 수 있다. 그러나 미국에 있는 만성 바이러스성 B,C형 간염을 가진  5.3 백만명은 50퍼센트 이상이  진단 미확정이다. 해볼만한 일은 스크린, 진단, 모니터, 그리고 심각한 문제들로 발전하기 전에 제때에 치료 하는것이다. HBV 치료는 이런 문제들을 치료할 순 없지만 막을 수 있다. 안타깝게도 미연방 투자기관에서 연구,실험,감독하고 정부에 의해 지원되는 치료 프로그램은 현재 총체적으로 부실하다. 

According to the National Viral Hepatitis Roundtable (NVHR), the proposed 2011 annual budget for CDC’s Division of Viral Hepatitis is only $21 million, just two percent of the overall budget for the National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention (NCHHSTP). Shockingly, this is less than the Division’s budget of $25 million from ten years ago (NVHR 2010).

국제 바이러스성 간염 토론회에 따르면, CDC의 바이러스성 간염 부서의 제안된 2011년 연간 예산은 단지 2천백만달러로, HIV/AIDS, 바이러스성 간염, 성병을 위한 국제 센터 전체 예산의 단지 2퍼센트이다.

심각하게도, 10년전 2천5백만달러 부서의 예산보다도 적다는 것이다.

Key provisions in the new healthcare reform law passed in March could help this dire situation. The insurance industry’s discriminatory practice of withholding coverage from people with pre-existing conditions will be banned by 2014. This means that people with chronic HBV can finally gain access to what will hopefully be affordable healthcare. However, implementation of the new legislation is expected to be an uphill battle, and will take a few years.

3월에 통과되는 법으로 새로운 의료 개정의 기본 조항은 이 긴박한 상황을 도울 것이다. 이전에 존재하는 상황의 사람들의 보상을 보류하는 보험 산업의 특별한 관행이 2014년부터 금지될 것이다. 이것은 만성 HBV를 가진 사람들이 마침내 바람직하게 저렴한 의료보험을 마침내 이용할 수 있다는 것을 의미한다. 하지만, 새 입법의 시행은 힘든 전쟁이 될 것이고 수년이 걸릴 것이다.

A recently released Institute of Medicine report (Colvin 2010) highlighted the lack of provider awareness about HBV contributes to the problem. Doctors often do not identify at risk people for screening, nor do they consult current guidelines on how and when to treat chronic HBV. According to one survey, 44 percent of primary care providers did not know HBV can be controlled with treatment.

최근 발표된 의학회 보고서는 문제를 야기하는 HBV에 관한 인식 제공자의 부족을 중요하게 다뤘다.

의사들은 만성 HBV를 치료할 때와 현재 가이드라인에 대한 방법으로 상담하지 않거나 검진으로 위험한 사람들을 종종 확인하지 않는다. 한 조사에 따르면, 우선 치료 준비자들의 44%가 치료되어야 하는지를 몰랐다고 했다.

Hopefully, the gradual expansion of access to health care will drive demand for new and better HBV treatment, and provide more financial incentives for the drug industry to invest in discovery and development of new compounds. In the meantime, there are no investigational new drugs in late stage development in the U.S. for HBV. Instead, the glimmer of hope—for what it’s worth—is coming from a handful of immune-based therapies, although these are all in early stage development.

바라건데, 건강 보험의 점차적인 이용 확장은 새롭고 더 나은 HBV 치료를 요구하도록 이끌 것이다. 그리고 새로운 합성물의 개발과 발견에 투자하고 약 산업을 위한 더 많은 재정적인 보조금을 제공할 것이다.

그 사이에, HBV를 위한 미국의 개발 마지막 단계에 까지 신약에 대한 조사는 없다. 대신, 가치있는 희미한 희망은 소수의 면역기반 치료요법이 나타나는 것이다, 비록 이 모든것은 개발 초기 단계에 있다.

Table 1. HBV Experimental Agents in the Pipeline

Agent	Manufacturer	Stage of Development	Class
Oral Antivirals
Emtricitabine (Truvada, in coformulation with tenofovir)	Gilead	Phase III/IV	NRTI
Clevudine	Bukwang/ Eisai	Phase III	NRTI
LB80380	LG Life Sciences	Phase IIb	NRTI
MIV-210 (Lagociclovir valactate)	Medivir/Daewoong	Phase II	NRTI
Simvastatin	University of Oklahoma Health Sciences Center/VA Medical Center	Phase I	3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor
Bay 41-4109	AiCuris	Pre-clinical	heteroaryldihydropyrimidine
Immune-based
Thymosin alpha (zadaxin)	SciClone Pharmaceuticals	Phase IV	Immunomodulator
Interferon gamma 1b (Actimmune)	InterMune	Phase II	Immunomodulator
CYT107 (recombinant human interleukin-7)	Cytheris	Phase I/IIa	Immunomodulator
DNA vaccine pCMVS2.S	ANRS (French Agency for Research on AIDS and Viral Hepatitis)	Phase I/II	Therapeutic vaccine
DNA vaccine (HB-110)	Genexine	Phase I	Therapeutic vaccine
Hepatitis B vaccine (Synthesized peptide PA-44)	Chongqing Jiachen Biotechnology	Phase I	Therapeutic vaccine
HBV DNA plasmid pdpSC18 vaccine	PowderMed/Pfizer	Phase I	Therapeutic vaccine
DV-601	Dynavax	Phase I	Therapeutic vaccine
Heplisav	Dynavax	Phase III	Preventive vaccine

Oral antivirals

구강 항바이러제들

Access to new brand-name drugs in Asia is limited by their prohibitive cost, an option only available in higher-income countries. The need for new drugs with better potency and higher resistance barriers are particularly pressing in the region, since lamivudine monotherapy has been the primary treatment for many years due to the availability of low-cost generics, and the drug’s weak resistance profile has contributed to wide-spread lamivudine resistance in people with chronic HBV. Although hepatitis B is endemic in Asia, there are only two oral antivirals in late stage development in China and South Korea.

아시아 인들에게 새로운 신약에 대한 접근은 과중한 비용에 의해 제한되어 진다, 단지 고소득의 나라들에서 단지 이용할 수 있는 선택이다. 더 좋은 효능과 더 높은 내성 장벽을 가진 신약을 필요는 지역에서 특히 절박하다. 라미뷰틴 단독 치료법은 일반적으로 낮은 소득의 사람들이 이용하기 때문에 수년간 주 치료가 되었다, 그리고 약재 내성 측면이 만성 HBV를 가진 사람들에게 라미뷰틴 내성을 널리 퍼지게 하는데 기여하였다.

Clevudine

Despite Pharmasset’s halting U.S. development of clevudine due to post-market reports of severe myopathy (muscle weakness) last year, the South Korean drug maker Bukwang is forging ahead with development and marketing plans for clevudine in Asia. Studies in South Korea and a phase III trial in China are underway. Bukwang’s Asian partner, Eisai Pharmaceuticals, has launched clevudine (brand name: Revovir) in the Philippines, with pending licensing plans for India, Indonesia, Malaysia, and Thailand. It will be up to doctors and regulatory authorities in these countries to keep a close eye on reports of myopathy, since the condition can develop after eight months of clevudine use, and people must stop taking it to avoid potentially fatal consequences. In a rapid communication published in Hepatology (Seok 2009), the main symptom of clevudine induced myopathy was slowly progressive muscular weakness in the limbs over several months. The condition can take up to four months to resolve after clevudine is stopped.

LB80380

LG Life Sciences published data from its safety and efficacy study of the new nucleotide analog LB80380 in Hepatology (Yuen 2010). The small study done in treatment-experienced Chinese volunteers with lamivudine-resistant chronic HBV showed potency comparable to entecavir and tenofovir, the two leading antivirals on the market. No significant drug-related toxicities were seen in this 12-week dose-finding study. A phase II study in treatment-naive volunteers is enrolling in South Korea and Hong Kong.

Tenofovir is the first-line treatment for lamivudine-resistant HBV in the U.S. and Western Europe. Resistance to tenofovir has not yet been characterized three years after the drug’s approval to treat HBV, but second-line drugs for people who become resistant to tenofovir may be needed in the future. Although LB80380 may be useful as a second-line drug for people with lamivudine resistance, an in vitro study revealed that LB80380 has only partial efficacy against adefovir and potential tenofovir resistant HBV strains. Development plans for the United States and Europe are unclear.

Emtricitabine/Tenofovir

This Gilead workhorse HIV combination pill is being studied in several ongoing HBV trials in different patient populations. Truvada is being studied in HIV/HBV coinfected people with a detectable HBV viral load despite current treatment, both in combination with pegylated interferon, and in a head-to-head comparison with entecavir. Trials are also underway in people with decompensated liver cirrhosis and liver transplant recipients.

Lagociclovir Valactate (MIV-210)

The Swedish drug maker Medivir has out-licensed MIV-210 to South Korean Daewoong Pharmaceutical to advance its development in Asia this year. This drug was initially developed for HIV and failed. Now it’s enjoying a second chance as an HBV treatment. MIV-210 has shown in vivo activity against lamivudine-resistant HBV strains in an animal model study done nearly ten years ago. Daewoong plans to launch a phase II study in South Korea.

Simvastatin

The University of Oklahoma and the U.S. Veteran’s Administration are conducting a phase I proof-of-concept study looking at the cholesterol lowering agent simvastatin, after in vitro data showed anti-HBV activity and synergistic activity when combined with approved HBV drugs (Bader 2010). The small three-arm study will compare simvastatin alone vs. simvastatin with either tenofovir or entecavir. Since the drug is available as a generic, it will radically change the current HBV market if proven effective on its own.

Bay 41-4109

Bayer’s Bay 41-4109 is a heteroaryldihydropyrimidine (HAP) that inhibits HBV assembly by interrupting viral capsid formation. The drug has recently resurfaced in an investor report from the German company AiCuris, a Bayer spin-off drug discovery company. Clinical development plans are unclear. Since it is the only experimental candidate that targets a different part of the viral life cycle than drugs currently on the market, the compound—if it is ever developed—could be used to treat drug-resistant HBV.

Bayer의 Bay41-4109는 바이러스 단백질 껍질을 방해함으로써 HBV 조립을 억제하는 HAP 약이다. 이 약은 최근에 독일 회사 AiCuris - Bayer 약 개발 자회사 - 로부터 투자자가 보고하여 다시 표면으로 떠 올랐다. 임상 전계는 불투명하다. 단지 시장에서 현재의 약들보다 바이러스 생존 주기의 다른 부분을 목표로 하는 실험적인 후보 이므로,  합성물은- 언젠가 개발된다면 - 약 내성 HBV를 치료하는데 사용될 수 있을 것이다.

Immune-based therapies 면역 기반 치료제들

CYT107

A new entrant from the immune-based front is French company Cytheris’ recombinant human Interleukin-7 (CYT107). This immunomodulator is also being studied for HIV and hepatitis C. The CONVERT study will compare CYT107 with the HBV preventive vaccine GenHevac B versus CYT107 alone in HBeAg negative patients on stable tenofovir or entecavir treatment. This phase I/IIa study is enrolling volunteers in France and Italy. The hope is that the agent will stimulate the immune system and restore immune response to HBV so that people do not have to stay on life-long antiviral therapy.

면역 기반 영역의 새로운 신약은 프랑스 회사 Cytheris의 재조합 휴먼 이터류킨-7(CYT107)이다. 이 면역

조절 물질은 또한 C형 간염과 HIV를 위해 연구되고 있다. CONVERT 연구는 안정적인 엔테카비어 또는 테노포비어의 치료에 있는 HBeAg 음성 환자에 단독 CYT107 과 비교하여  HBV 면역 백신 GenHevac B와 CYT107 을 비교할 것이다. 이 임상 1/2단계는 프랑스와 이탈리아에서 참가자들을 등록하고 있다.

작용제는 사람들이 장기간 항바이러스 치료를 유지하지 않도록 하기 위해서 HBV에 대한 면역 반응을 회복하고 면역 체계를 자극 할것이라는 희망이다.

Several other immunomodulators and therapeutic vaccine candidates are currently in early phase development; however no study data have been published in the past year. For detailed descriptions of these agents, please see TAG’s 2009 Pipeline Report.

몇몇 다른 면역 조절 물질과 치료 백신 후보들은 현재 개발단계 초기에 있다.; 하지만 과거동안 연구 자료가 발표되지 않았었다. 이 작용제의 세부적은 설명을 보려면, TAG'의 2009 파이프라인 보고서를 보세요.

·         Interferon gamma 1b (Actimmune)—A phase II study of this chemically manufactured form of human interferon gamma has not yet opened for enrollment.

·         Thymosin alpha1 (Zadaxin)—A phase IV trial of this synthetic version of a substance produced naturally by the thymus is still active in South Korea.

·         HBV naked DNA vaccine pCMVS2.S HBV—A phase I/II study is still ongoing with completion expected in late 2010.

·         Mixed plasmid DNA (HB-110) vaccine—A phase I study combining the vaccine with adefovir is still enrolling patients in Korea.

·         Hepatitis B vaccine (synthesized peptide PA-44)—A phase I study in China is still ongoing.

·         HBV DNA plasmid pdpSC18 vaccine—A phase I study has been completed but no data are published as yet.

·         DV-601—A phase I study is open and enrolling patients using this therapeutic vaccine being developed by Dynavax in Europe.

Preventive vaccine  예방 백신 

Heplisav

Dynavax successfully resuscitated this preventive vaccine after a series of setbacks. After the U.S. Food and Drug Administration (FDA) placed a clinical hold on the development of Haplisav in 2008 due to a case of vasculitis (inflammation of the blood vessels), a potentially deadly autoimmune condition also known as Wegener’s granulomatosis, Merck pulled out as a development partner. Dynavax was able to convince the FDA to release the hold by redesigning its development to target the vaccine for subsets of people with immune deficiencies that render currently approved HBV vaccine ineffective, altering the risk-versus-benefit equation to favor development. The company has since launched two large-scale phase III studies, one in people with end-stage renal disease, and the other in people over the age of 40. While this vaccine could be helpful to some HIV-positive people who do not achieve protective immunity with currently approved vaccines, no study in HIV-positive people is being planned. The vaccine will require only two shots within one-month, compared to the current standard of three shots in six months. It has demonstrated non-inferiority with GSK’s Engerix-B vaccine, and data from the two phase III studies are expected in mid-2011.

 Dynavax는 수많은 실패 뒤 이 예방 백신을 성공적으로 탄생시켰다. 미국 식약청(FDA)는 맥관염(혈관 염증) - 배게너육아종증으로 알려진 잠재적으로 치명적인 자기면역 상태, 때문에 2008년에 Haplisav의 개발에 대한 계속적인 임상이 정해진 후, Merck사가 개발 파트너로서 뽑혔다. Dynavax는 FDA가 개발을 찬성하는 위험 대 이익의 대등함쪽으로 변해가면서 현재 비효과적인 승인된 HBV 백신을 양도하는 면역 결핍인 사람들의 소그룹을 위한 백신을 타겟으로 하는 Dynavax의 개발을 재 디자인 함으로써 소유권을 공개할 것을 확신할 수 있었다. 회사가 대규모의 임상 3상 연구가 시작된 이후로, 마지막 단계의 사람들 중 한명이 신장병 그리고 다른 사람들은 40살 이상이었다. 하지만 이 백신이 현재 승인된 백신으로 면역을 보호하지 못하는 에이즈 양성인 사람 몇 명에게 도움을 줄지도 모르지만 에이즈 양성인 사람들이 계획된 연구는 없다. 이 백신은 여섯달에 세 번 주사인 현재 표준과 비교해서 한 달에 두 번 주사 될 것이다. GSK의 Engerix-B 백신과 비교해 뒤지지 않음을 증명했다. 그리고 두 임상 3단계 연구들의 자료는 2011년 중반이 예상된다.

Hepatitis B Clinical Research Network

The anticipated opening of the Hepatitis B Clinical Research Network’s first trials at the end of 2009 did not materialize. Reportedly, the delay is due to complex contract negotiations with drug and diagnostic companies regarding provision of drugs and funding. This delay is disappointing, as several of the Network’s planned trials will address many research questions critical to our understanding of chronic HBV disease progression, as well as optimal treatment strategies with currently available drugs. TAG hopes the negotiations will be completed quickly so as not to impact the duration of these studies, since the network is nearing the start of the third year in the seven-year grant from the U.S. National Institutes of Health (NIH) without enrolling a single patient.

References

Bader T, Korba B. Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro. Antiviral Res. 2010 Jun;86(3):241-5.

CDC. Hepatocellular Carcinoma—United States, 2001–2006. MMWR: Morbidity and Mortality Weekly Report 2010;59:17

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NVHR. National Viral Hepatitis Roundtable Warns “Systemic Underfunding” of Federal Viral Hepatitis Programs Puts Five Million Americans at Risk. Press release. March 16, 2010

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