Brincidofovi有望成为器官移植患者的抗病毒首选药物
2015-03-06 09:34:30 来源 Cathy
2015年3月6日讯 /生物谷BIOON/ -- 一般而言，腺病毒不会对人体健康造成大的威胁，因为人体免疫系统就可以应对它所引起的呼吸或消化系统感染，但对于骨髓移植或其他器官移植的病人，腺病毒感染往往是致命的，死亡率高达80%。
市场上尚且没有经FDA批准的腺病毒治疗药物。临床医生往往会选择静脉注射产品Cidofovir（西多福韦），该药物本来是用来治疗AIDS患者发生的眼部巨细胞病毒感染。但Cidofovir副作用明显——肾功能损害。
Brincidofovir是Chimerix正处于临床研究阶段的产品，在埃博拉的治疗方面引起广泛关注。除了对埃博拉病毒有抗病毒作用，Brincidofovir还对腺病毒有一定杀伤作用，相关临床试验已经进行了大部分，现正处于末期阶段。一年前，一名频繁进行癌症放化疗的7岁小孩Josh Hardy接受了骨髓移植，但发生了严重的腺病毒感染，新闻媒体及社会舆论建议Chimerix给这名小孩“同情用药”Brincidofovi，于是他也就成了末期临床试验的第一个对象。
Chimerix表示临床试验绝对遵循金标准，试验对象都是从未接受过相关药物治疗的腺病毒感染者，采取双盲实验法。Chimerix医疗事务负责人Garrett Nichols说他们曾遇到了很大的困难，医疗中心及受试者对该项目有些排斥，因为对照组病人服用的是安慰剂，不具有抗感染功效，很可能就因此丧命，而每位受试者都有50%的可能成为对照组。去年这个时候，Chimerix已将Brincidofovi对腺病毒的临床试验进行到了中期阶段，但如何推进末期试验还存在很大争论，而那名叫作Hardy的小孩的出现直接推动了末期临床试验。现在，临床试验已经不再设对照组，而是采取“历史对照”——拿以前的腺病毒案例作为对照。“历史对照”是致命疾病临床试验常用的方法，选取的试验组成员与历史对照的案例在同一个地方接受过相同的器官移植。
Cidofovir是吉利德的产品，能阻止病毒的复制，但该药能被一种蛋白质识别携带入肾，造成肾损伤。而Brincidofovi不会入肾，所以没有肾毒性。Brincidofovi实际上是Cidofovir分子上加载了一个脂分子，做成片剂，口服，经肠胃吸收，所以生物利用度比Cidofovir好很多。
Brincidofovi三期临床已经采集了85名参与者的数据，试验组给药75天后，死亡率37%。有一定副作用——引起腹泻，但发生率并不高，对肾脏及骨髓并没有什么不良影响。参与研究的有成人，也有儿童，受试者队伍将逐步扩大到200人。
除了腺病毒，Brincidofovi对其他病毒有无杀伤力？Chimerix已经组织了相关临床试验，比如对巨细胞病毒感染的治疗。将来向FDA递交申请时会同时递交两方面的资料。此外，在临床实验中，有些受试者还感染了其他病毒，似乎也受到抑制。“看起来Brincidofovi作用范围很广。”Chimerix发言人说道。（生物谷Bioon.com）
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英文原文：
Chimerix Drug Shows Promise As Virus Fighter for Transplant Patients
The commonly found adenovirus poses little problem for healthy people， whose immune systems can fight the respiratory and gastrointestinal infections the virus can cause. But in bone marrow and organ transplant patients， adenovirus often becomes deadly. Their weakened immune systems can’t fight off the virus， which studies show can be fatal in up to 80 percent of such cases.
There are no FDA-approved drugs to treat adenovirus， leaving some doctors to turn to a different drug that is associated with a high risk of kidney damage. But an experimental antiviral developed by Durham， NC， pharmaceutical company Chimerix (NASDAQ： CMRX) is showing potential as a safer alternative. A late-stage clinical trial is still underway and Chimerix is taking an unusual approach to the study， but early results show that the Chimerix drug brincidofovir cut adenovirus mortality rates by more than half.
If the Chimerix drug sounds familiar， it might be in the context of Ebola. Brincidofovir was in the spotlight last fall as one of several experimental antiviral drugs pressed into emergency use treating Ebola patients. But a year ago， Chimerix found itself in the spotlight for a different reason. Then 7-year-old Josh Hardy， whose body was weakened by cancer treatment and a bone marrow transplant， was dying from adenovirus infection. A “#SaveJosh” social media campaign and nationwide news coverage built pressure on the tiny company to release the still unapproved drug under so-called compassionate use. The Virginia boy was eventually administered brincidofovir—not under compassionate use but as the first patient in a late-stage trial of the drug.
Chimerix
The gold standard of drug testing in diseases where no treatments are yet available is a double-blind study that compares patients who receive the experimental drug against a second group receiving only a placebo. But Garrett Nichols， Chimerix’s chief medical officer， says treatment centers and their patients are reluctant to participate in studies where some participants receive only a sham treatment because adenovirus is so deadly for these patients.
The idea gave Chimerix pause as well. “It’s difficult to imagine doing a placebo-controlled trial for an infection with 60 to 80 percent mortality，” Nichols says.
At this time last year Chimerix， which had already taken brincidofovir as far as mid-stage clinical trials in adenovirus， was discussing with the FDA what a late-stage study would look like. Hardy’s case gave the company and regulators “that extra push，” he says， toward agreement on a clinical trial design.
Chimerix is now studying its drug in transplant patients， like Hardy， who have adenovirus infection. But instead of comparing the treatment group against a placebo group， Chimerix is using “historic control.” The group of patients treated with the Chimerix drug will be compared against historic data of adenovirus cases.
Historic controls are typically reserved for drug studies in fatal diseases， such as some rare cancers， Nichols explains. In an effort to make the data as comparable as possible， the adenovirus patients will be compared against those who received the same types of transplants and were treated at the same sites where the current trials are taking place.
In the absence of an FDA-approved treatment for adenovirus， many physicians turn to the intravenously administered drug cidofovir (Vistide)， says Michael Grimley， a pediatric hematologist/oncologist at Cincinnati Children’s Hospital Medical Center. The drug is approved to treat cytomegalovirus eye infections in AIDS patients. But Grimley， who is also the principal investigator of the Chimerix adenovirus trial at Cincinnati Children’s， adds that without any alternatives， some physicians consider cidofovir the standard of care for treating adenovirus. The drug， however， brings the risk of kidney damage.
“Everybody I’ve treated with IV cidofovir has significant renal impairment from the treatment and that is troubling，” he says. “It’s a double-edged sword. What you do to get your immune system better has other troubling complications.”
Cidofovir， which is marketed by Gilead Sciences (NASDAQ： GILD)， interferes with the way that viruses make copies of themselves. But that drug is also picked up by a protein that takes it right to the kidney， leading to kidney damage， Grimley explains. Brincidofovir never latches on to that protein so the kidney never sees the cidofovir.
To produce brincidofovir， Chimerix binds cidofovir with a lipid molecule that makes it absorbable in the gut. This means Chimerix can make its drug into a pill—something that is not possible with regular cidofovir， Nichols says. The lipid also shepherds the drug directly into the target cells， where it then releases the cidofovir molecule， which means that those cells receive much higher levels of the drug compared with intravenous cidofovir.
The Chimerix drug was developed in the laboratory of Karl Hostetler at the University of California San Diego. Hostetler developed the lipid technology under a government contract for use in a smallpox antiviral. That program， funded by the Biomedical Advanced Research and Development Authority， continues at Chimerix today. Chimerix’s work in transplant patients came from the company’s search for other applications of its drug.
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adenovirus
Adenovirus
So far， Chimerix has data from 85 patients who received brincidofovir in its Phase 3 adenovirus study. In the study， the mortality rate in bone marrow transplant patients with disseminated adenovirus infection was 37 percent after 75 days. Brincidofovir has gastrointestinal side effects， including diarrhea. Grimley says those side effects were known but they occurred less frequently compared with their occurrence in an earlier study. Three patients dropped out of the Phase 3 trial due to those side effects， but Grimley says it’s possible that they were instead suffering the effects of adenovirus in their intestinal tract. Most important， he says， there was no evidence of damage to the kidneys or bone barrow. The study， which is enrolling both children and adults， is expected to include 200 total patients.
Chimerix hopes that brincidofovir finds applications in other viruses. The company is also in a separate late-stage clinical trial studying the drug’s ability to prevent cytomegalovirus infection in bone marrow transplant patients. This placebo-controlled study will be important in filing for FDA approval of the drug， Nichols explains， since Chimerix plans to file drug applications in adenovirus and cytomegalovirus at the same time. Nichols says efficacy and safety data from the cytomegalovirus trial will help support the company’s submission of the drug in adenovirus. The company expects to have data from the cytomegalovirus study in about a year.
Meanwhile， the adenovirus study results so far help support Chimerix’s case for applying brincidofovir in multiple viruses. Grimley says half of the patients enrolled in the adenovirus study suffered from additional viral infections.
“Brincidofovir worked on those as well，” he says
