Wednesday, November 9, 2011

Protons, Electrons, and Hepatitis C

Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).

The Latest Findings
There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.

PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.

After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.

Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.

Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.

The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.

In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.
Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.

Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.

Other New Drugs for Hepatitis C

If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied.

These include:
• Second-generation protease inhibitors (telaprevir and boceprevir are protease inhibitors) such as TMC435, danoprevir, GS 9256, BMS 791325, ACH-1625, MK-7009, and BI 201335
• Inhibitors of nonstructural protein 5A, which is involved with viral replication. BMS 790052 is one such compound currently being evaluated
• R7128, another nucleoside polymerase inhibitor (same class as PSI-7977)
• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)
• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.
• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.

HCV and the History of the Human Race

On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm.

For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.

But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s.

(Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.

Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the CDC’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)

Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.

You see?

There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.

There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?

Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.

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