New Hepatitis C Drug, RNAi drugs: microRNA-122
"Traditional drugs are small chemicals that bind directly to the pathogen's machinery. In contrast, RNAi drugs are little fragments of RNA (or DNA) that act like "sponges" inside the cell. They mop up other RNA molecules that a virus or cancer cell needs to survive."
"The pharmaceutical industry has been working for decades to get RNAi drugs to work, says Dr. Judy Lieberman of Harvard Medical School, who wasn't involved in the current study. "At first there was wild enthusiasm - and billions of dollars," she tells Shots. "Hundreds of companies became involved because these drugs could be a whole new class of therapeutics for all kinds of diseases." But enthusiasm and money waned over time, as companies realized it wasn't going to be easy to get these drugs to work. Pharmaceutical giants, like Roche and Novartis, pulled the plug on million-dollar programs back in 2010, the journal Nature reported. But a few companies stayed the course. And, recently, there have been hints of success."
"But the safety of using miravirsen for long periods at high doses remains a question for further research, Lieberman and Sarnow wrote: As it happens, miravirsen targets a bit of genetic material that helps suppress the development of fatty liver, liver fibrosis and liver tumors, all of which are side effects of hepatitis C infection as well."
Hepatitis C drug goes after patients' RNA
Compound targets genetic material that virus uses for replicating
By Nathan Seppa
Web edition: March 27, 2013
No matter what medications doctors throw at hepatitis C, it continues to defy treatment in some patients. But a new compound offers an approach quite apart from the rest: It assaults a kind of RNA that is implicated in allowing the virus to gain a foothold.
In most of a small group of patients who took the experimental drug, virus levels were knocked down, sometimes below the threshold of detection. The drug does this by targeting genetic material in the liver called microRNA-122. The hepatitis virus normally attaches to this RNA, gaining the stability it needs to propagate while hiding from immune system patrols.
The new drug, called miravirsen, binds to microRNA-122, sequesters it and indirectly thwarts viral replication, says study coauthor Harry Janssen, a hepatologist and physician at the University of Toronto. Janssen and colleagues report the findings March 27 in the New England Journal of Medicine.
The technique could have broad applicability, because microRNAs - genetic material that regulates some gene activity - can play roles in cancer and other ailments (SN: 8/28/2010, p. 18). The strategy is "a whole new approach to the treatment of serious disease," says Phillip Sharp, a molecular biologist at MIT who earned a 1993 Nobel Prize for work on RNA. "This is an additional treatment that looks quite interesting and almost certainly will be used at some level," he says.
For the study, researchers randomly assigned 36 people with hepatitis C to get five weekly injections spaced over a month. Nine were given placebo shots while 27 got varying doses of miravirsen. No study participant had received any hepatitis drugs beforehand. The scientists monitored the patients for 18 weeks.
While those given the placebo showed little or no improvement, most who received the drug experienced a drop in virus levels. The 18 patients at the two highest dose levels showed profound reductions in viral RNA during the study period. Five of those 18 patients had undetectable virus levels at some point after treatment.
A few patients in each subgroup also received interferon - a standard treatment for hepatitis C - during the trial. At the end of the study, four patients getting both drugs and one getting miravirsen alone still showed no detectable virus - 14 weeks after the last shot.
Some experts worry that because microRNA-122 affects certain liver functions - including cholesterol synthesis - a drug inhibiting the microRNA might cause serious side effects. But patients in this trial showed only mild effects.
In the body, miravirsen has a half-life of roughly 30 days, Janssen says, suggesting that it might work as a monthly injection. Pairing it with another medicine might work even better, he adds. The new drug may dodge viral resistance to current drugs because it targets the host, not the virus.
MicroRNAs were discovered only 20 years ago, and research in the field is moving rapidly, Sharp says. "This is really a revolution in science," he says, "and it's now beginning to be translated into advances that control disease."
MicroRNA HCV Therapy Has Big Promise
By Michael Smith, North American Correspondent, MedPage Today
Published: March 27, 2013
· A nonpharmaceutical approach to hepatitis C (HCV) treatment demonstrated promising efficacy and safety results in an early stage trial.
· Point out that the antisense oligonucleotide miravirsen, which binds miR-122, had no dose-limiting adverse events and did not appear to give rise to resistance.
A nonpharmaceutical approach to hepatitis C (HCV) treatment demonstrated promising efficacy and safety results in an early stage trial, researchers reported.
Blocking the liver-expressed microRNA-122 (miR-122) led to dose-dependent and persistent declines in HCV, according to Harry Janssen, MD, PhD, of the University Health Network in Toronto, and colleagues.
The antisense oligonucleotide miravirsen, which binds miR-122, had no dose-limiting adverse events and did not appear to give rise to resistance, Janssen and colleagues reported online in the New England Journal of Medicine.
The researchers noted that miR-122 binds to two sites in the HCV genome - an attachment that is essential for the "stability and propagation" of the virus. Miravirsen, in turn, binds to miR-122, making it unavailable to HCV.
Their findings - from a randomized, double blind, placebo-controlled, Phase IIa study - suggest that miravirsen might play a role in treating chronic HCV infection, the researchers concluded.
But exactly what that role is will depend on further study, experts outside the industry-supported study commented.
The results so far are "very exciting," according to Stacey Rizza, MD of the Mayo Clinic in Rochester, Minn.
"One of the challenges in hepatitis C is always resistance," she told MedPage Today. "These microRNA (inhibitors) are targeting very conserved parts of the hepatitis virus so the chance of resistance is much lower."
But, she cautioned, "It's still very early, we don't know if it's actually going to lead to the outcomes we need it to lead to -- i.e. cure - and we're not sure yet long-term whether this is going to be safe."
Indeed, the long-term safety of the substance may be important, since one of the functions of miR-122 is to act as a tumor suppressor, commented Judy Lieberman, MD, PhD, of Harvard Medical School, and Peter Sarnow, PhD, of Stanford University in Palo Alto, Calif.
But, they concluded in an accompanying editorial in the journal, "pending satisfactory answers to the questions regarding safety," miravirsen or other microRNAs might be useful in a cocktail of anti-HCV agents that would have various targets.
Miravirsen, Janssen and colleagues reported, suppressed HCV in animal studies and showed no adverse events in healthy volunteers. To advance the clinical trials, they enrolled 36 treatment-naïve patients with genotype 1 HCV and randomly assigned them to placebo or one of three doses of miravirsen -- 3, 5, or 7 milligrams per kilogram of body weight.
Patients got five subcutaneous injections over a 29-day period and were followed for 18 weeks.
Miravirsen, they reported, led to dose-dependent reduction in HCV RNA, Specifically, the average maximum drop in HCV RNA (in log10 IU per milliliter) was:
· 1.2 for patients receiving 3 milligrams per kilogram, a change that was significant (P=0.01).
· 2.9 for those getting 5 milligrams per kilogram ( P=0.003).
· 3.0 for patients given 7 milligrams per kilogram, (P=0.002).
· 0.4 in the placebo group.
During the 14 weeks of follow-up after the end of treatment, HCV was not detected at some points in one patient in the 5-milligram group and in four patients in the 7-milligram group.
Several of those patients had viral rebound, suggesting that 4 weeks of miravirsen is not enough to lead to sustained virological responses, Janssen and colleagues reported.
Only two of the 112 adverse events reported miravirsen patients were above grade 2, the researchers reported, but none was dose limiting.
As well, the researchers reported that they found no mutations in the miR-122 binding sites of the HCV genome that would lead to resistance.
Rizza told MedPage Today that therapy for HCV is advancing rapidly, to the point where investigational all-oral regimens are possible that avoid the standard but difficult-to-take pegylated interferon and ribavirin.
But even those novel regimens may not be useful in all patients, so a therapy like miravirsen is likely to find a role, she said.
'Sponge' Drug Shows Promise For Treating Hepatitis C
NPR by Michaeleen Doucleff
March 27, 2013 6:16 PM
Particles of the hepatitis C virus are imaged with an electron microscope.
With an estimated 2 million baby boomers infected with hepatitis C, the disease has reached epidemic levels among Americans age 48 to 68.
Doctors can now cure about 70 percent of hepatitis C cases, but the drugs' side effects can be severe. And many Americans are still left with a disease that can cause liver failure and cancer.
So doctors have been desperate for better treatment options.
One of the drugs in the pipeline, called miravirsen, may be able to stop the virus with little side effects, doctors from University Health Network in Toronto, Canada, reported Wednesday.
Their findings, published in The New England Journal of Medicine, are preliminary - the doctors gave the drug to just 27 patients for about a month. (Another 9 patients in the study were given a placebo.) But the study is still drawing attention because it offers proof-of-concept for a whole new class of drugs, called RNA interference drugs.
RNAi drugs work differently than traditional antivirals and antibiotics. And some scientists think they may have the potential to treat many illnesses, including the big killers, cancer and heart disease.
Traditional drugs are small chemicals that bind directly to the pathogen's machinery. In contrast, RNAi drugs are little fragments of RNA (or DNA) that act like "sponges" inside the cell. They mop up other RNA molecules that a virus or cancer cell needs to survive.
The pharmaceutical industry has been working for decades to get RNAi drugs to work, says Dr. Judy Lieberman of Harvard Medical School, who wasn't involved in the current study.
"At first there was wild enthusiasm - and billions of dollars," she tells Shots. "Hundreds of companies became involved because these drugs could be a whole new class of therapeutics for all kinds of diseases."
But enthusiasm and money waned over time, as companies realized it wasn't going to be easy to get these drugs to work.
Pharmaceutical giants, like Roche and Novartis, pulled the plug on million-dollar programs back in 2010, the journal Nature reported. But a few companies stayed the course. And, recently, there have been hints of success.
In January, the Food and Drug Administration approved the first RNAi drug, Kynamro (brand name mipomersen sodium), to help people with an extreme type of high cholesterol.
Now the current study on miravirsen offers hope for hepatitis C. "It's the first example of really strong clinical evidence" that the RNAi therapies are going to work in people, Lieberman says.
It's too soon to say how effective miravirsen is compared to current hepatitis C treatments, says Dr. Harry Janssen, who led the study. The goal of the current trial was to figure out how much miravirsen is needed to stop the virus temporarily - not it's overall effectiveness. That will require a bigger study.
Four of the nine patients who got the highest dose of miravirsen temporarily cleared the virus after five injections. "That compares very well to current treatments," Janssen says.
But unlike many medications available now, the RNAi drug works on all types of hepatitis C, even those that are tough to treat. And the short-term side effects are minimal - a rash and pain at the injection site.
Still, Janssen and his team don't know what the long-term effects could be and exactly how to combine miravirsen with other medications. And, he says, there are other hepatitis C drugs in the pipeline that are closer to getting approval.
"So I think our study is a big step forward for hepatitis C, but a bigger step forward for medicine in general," he says. "It opens big avenues for using this concept [RNAi drugs] in humans."
A new drug shows promise of hepatitis C cure
LA Times By Melissa Healy
March 27, 2013, 4:42 p.m.
In findings that may represent a breakthrough in the treatment of hepatitis C infection, researchers have reported that weekly injections of an experimental medication that denies the virus a foothold in the liver substantially drove down subjects' viral loads after five weeks of treatment. Fourteen weeks after the injections ended, researchers found that five of 18 infected subjects getting the medication's higher doses showed no detectable trace of infection.
The new study describes a treatment approach that could outsmart the hepatitis C virus's penchant for developing resistance to existing drugs and "provide curative therapy to a large proportion" of the 170 million people in the world who are infected with the virus, wrote Harvard University physician Dr. Judy Lieberman and Dr. Peter Sarnow of Stanford University.
The treatment, called miravirsen, does so by targeting the "Achilles' heel" that is common to all of the hepatitis C virus' diverse strains--their universal need to colonize certain bits of protein that turn genes on and off in the liver.
Miravirsen is an antisense oligonucleotide: It enters the liver cells and binds tightly to those messenger proteins the hepatitis C virus needs to survive and replicate. By denying the virus its host, miravirsen could leave the virus homeless.
Even the wiliest strains of the virus would be locked out of the sanctuary they need to develop resistance to protease inhibitors such as teleprevir and boceprevir. And that, in turn, could free hepatitis C patients from the need to take interferon and ribavirin, which come with such side effects as fatigue, flu-like symptoms, anxiety, depression, diarrhea and nausea.
But the safety of using miravirsen for long periods at high doses remains a question for further research, Lieberman and Sarnow wrote: As it happens, miravirsen targets a bit of genetic material that helps suppress the development of fatty liver, liver fibrosis and liver tumors, all of which are side effects of hepatitis C infection as well.
Such safety concerns might limit the sweeping promise of miravirsen to cure hepatitis C infection in all its forms, Lieberman and Sarnow said. But even then, it could become part of a cocktail of antiviral medications that, collectively, could hold such infections in check. And on the plus side, they noted, miravirsen appeared to have the effect of lowering cholesterol in subjects -- a particular advantage because hepatitis C sufferers taking protease inhibitors cannot take cholesterol-lowering statin drugs.
The new research, as well as Lieberman and Sarnow's assessments of its promise, were published Wednesday on the New England Journal of Medicine's website.