How Can "JAK Inhibitors" Help Salvage Patients and the Search for an HIV Cure?

This interview was conducted in June 2012.

As part of my work as an HIV cure and salvage treatment activist, I am constantly searching for treatment options that could serve two purposes: help patients with multidrug resistance, and at the same time be used as an approach to cure HIV. Since my nonprofit, Program for Wellness Restoration (PoWeR), has a very small budget for me to attend conferences, I rely on the summaries that Jules Levin and his group at National AIDS Treatment Advocacy Project (NATAP) publish after he attends conferences. I am glad Jules can serve as eyes and ears for those of us who are unable to attend so many important scientific meetings.

Rarely do I come across information about a drug that is already available and that can treat HIV and hopefully also help decrease its reservoirs. While reading one of NATAP's great summaries about the International Workshop on HIV and Hepatitis, which was held in Sitges, Spain, from June 5-9, I came across a completely new approach that could meet the two goals.

One of the abstracts presented by Raymond F. Schinazi, Ph.D., D.Sc., and colleagues was on the topic of a novel series of inhibitors of HIV replication called JAK inhibitors. The JAK-STAT pathway is routinely stimulated in HIV-infected cells and can therefore be perceived as a logical target for drug development. Dr. Schinazi's proof-of-concept study showed that two compounds termed tofacitinib (trade name: Xeljanz; approved by the U.S. Food and Drug Administration [FDA] for rheumatoid arthritis in November 2012, after this interview was conducted) and ruxolitinib (trade name: Jakafi; approved by the FDA for myelofibrosis) demonstrated excellent inhibition of HIV replication at very low concentrations in vitro, as well as against replication of SIV in rhesus macaques. Moreover, these compounds were not toxic at the very low doses required for virus control. The data also suggest that these compounds might interfere with the ability of HIV to achieve latency in a variety of target cell types, and that they were active against all of the variety of forms of drug-resistant HIV that were tested. In addition, these compounds seem to re-activate latent virus hidden in reservoirs, which may help with the "flush-and-kill" approach being studied as part of HIV cure research.

Dr. Schinazi is the Frances Winship Walters Professor of Pediatrics and director of the Laboratory of Biochemical Pharmacology at Emory University. Dr. Schinazi is the founder of several biotechnology companies focusing on antiviral drug discovery and development, including Pharmasset, Triangle Pharmaceuticals, Idenix Pharmaceuticals, and RFS Pharma. He has published over 400 peer-reviewed papers and seven books, and holds more than 100 U.S. patents. He is best known for his innovative and pioneering work on emtricitabine (FTC, Emtriva), lamivudine (3TC, Epivir), stavudine (d4T, Zerit), telbivudine (LdT, Tyzeka), and DAPD (amdoxovir), drugs that are now approved by the FDA or are at various stages of clinical development. His inventions now sell more than US$2.0 billion per year and more than 94% of HIV-infected individuals take at least one of the drugs he invented. Dr. Schinazi has served on the Presidential Commission on HIV and currently serves on the board of trustees of amfAR. Due to his many business accruals and notable academic accomplishments, Dr. Schinazi is internationally recognized as one of the most influential persons in the life science sector.

I contacted Dr. Schinazi and he was happy to speak to TheBodyPRO.com about his findings.

Dr. Schinazi, thank you so much for taking the time to talk to us at TheBodyPRO.com. When I did a search on the Internet about your work, I was blown away. I'm just blown away by all the work, all the patents, published papers and the books. So thank you, because I know you must be a busy person.

It's no problem. I'm well known actually in the scientific world, not in the public. I try to keep a low profile, usually, which is hard because when you search my name on the Internet, you probably find so much, but not everything there is true.

I have to say I've been positive for 27 years, and your work has definitely made a difference in my life.

Well, if you're HIV infected, it's very likely you're taking one of my drugs. So I am happy to have been of assistance to you personally.

Yes, of course, you definitely have.

I'm also the founder of Pharmasset, which is the company that has one of the best phase 3 HCV [hepatitis C] drugs which was sold in January 2012 for $11.4 billion to Gilead. I believe this drug will also save a lot of lives and cure a lot of people from this devastating infection that affects 3% of Americans.

Now we're working on curing HIV, so that's why I think what we're doing here with this JAK inhibitor is really important.

It's amazing what you've done. Could you please tell us about the abstract that you presented at the International Workshop on HIV and Hepatitis in Sitges about JAK inhibitors?

There's this pathway called the JAK-STAT pathway, which is very important for HIV, because it is activated upon HIV infection. So, anything you can do to suppress it is a good thing, very simply. Basically, inhibition of the JAK-STAT pathway in addition could provide a mechanism to do several things. One, something we didn't expect, it could inhibit HIV replication in HIV-infected cells. And actually that was something we discovered for the first time: demonstrating this JAK inhibitor had intrinsic anti-HIV activity.

In addition, the JAK inhibitor renders bystander cells less susceptible to HIV infections by regulating the activation stage. In activation stage, basically the normal cells that are surrounding the infected cells become less susceptible to HIV, which is a good thing because it prevents the virus from spreading to these cells. It also prevents the recruitment of uninfected cells to the site of infection.

A really major mechanism of the JAK inhibitors is they reduce inflammation also. There are a whole bunch of pro-inflammatory cytokines that thrive when HIV infects the cells and JAK inhibitors can ablate these effects. This is not something new; we have known for some time the mechanism of these JAK inhibitors. They are used primarily for rheumatoid arthritis and autoimmune psoriasis. They are used for various cancers and one of them is actually approved for myelofibrosis. All these facts put together make these compounds amenable for testing to help suppress HIV and also reduce inflammation.

I think inflammation is a very important factor in HIV infection, not only at the site of infection, wherever active virus is, but also for cardiology; and as you know, there has been a strong relationship between the heart and HIV -- people even have sudden death. In a recently published paper that came out, people die from heart attacks or cardio disturbances because they're HIV infected. So, it is a good thing that these compounds could reduce the inflammation in addition to preventing the virus from replicating, preventing the virus from spreading and also suppressing virus replication at the cellular level unlike normal antiviral agents, which basically interfere with the virus machinery and ability to replicate themselves. Basically, after working on the virus, these JAK inhibitors also act on cellular mechanisms associated with inflammation.

There are a lot of people involved in trying to cure HIV. They are actually activating the latently infected cells and trying to destroy them since they now become visible to the immune system -- trying to destroy the cells and the virus contained in these cells. Despite activating the virus from these cells, the cells are not totally destroyed; so all these approaches, in my personal opinion, will probably not work. So, I am concerned about this and I'm sure you've written about this before or you've spoken to other people. So, I'm thinking differently and during the Sitges meeting I was the only person talking about suppressing HIV rather than activating this virus.

We have in our body maybe 50 to 100 viruses right now and most of them are suppressed. They don't bother us and that's why we can live a normal life. When our immune system is debilitated, the viruses come out. For example, chicken pox infection is common when you're a kid, but the same virus becomes varicella-zoster when you're older. We have viruses all over our body, like we have bacteria too all over our body; so nothing's new there. My philosophy is to suppress, and end up with a "functional cure." That's what I'm interested in: a functional cure, rather than an eradication cure. This is going to be very hard to do. Even with the Berlin patient [Timothy Brown], as you well know, it's been extremely hard to prove a negative, i.e., that the patient is really cured and that there is no trace of virus in his body.

There is residual RNA or DNA present in the body of the Berlin patient that we don't quite understand. I'll call his cure a "functional cure," not actually a complete cure, despite what people may say. However, there is hope that you can actually do it and we would like to try to use the best JAK inhibitors. As I said, one of them is approved: Jakafi is approved by the FDA, which is used for myelofibrosis. Eventually, this drug will also be approved for rheumatoid arthritis, autoimmune psoriasis and also various other kinds of conditions. There are other drugs that are being developed in the same class for rheumatoid arthritis that will basically replace injectable anti-TNF-alpha therapy, which as you know can reduce inflammation, but with a number of side effects. So again, these are new modern drugs which are coming out that have this utility that we're trying to apply for HIV.

I was reading about a JAK inhibitor called tofacitinib, a drug made by Pfizer that got reviewed [in May] for a rheumatoid arthritis indication. I guess this drug will probably be approved by the FDA soon. It looks pretty good -- low side effect profile and BID [twice daily] dosing. I was looking at the in-vitro data you presented at the conference. The dose you used ranged from 0.02 to 0.3 µM. How does that dose translate if used in humans? Also, are you proceeding with studies in humans?

[Editor's note: Xeljanz (tofacitinib) was approved by the FDA to treat adults with moderately to severely active rheumatoid arthritis, in November 2012.]

These drugs are given as a dose of 20 mg per day -- very small pills, because at a higher dose they'd probably have some side effects. We will plan on using initially the smallest doses and they come in different sizes. I foresee using different inhibitors of different JAK pathways for patients who are infected with HIV. What we do now is that the JAK inhibitors could be dosed to provide blood levels in the nM range. As mentioned, one is already approved for chronic long term use in humans, which is important. Interestingly, some of these compounds, but not all of them, are CYP3A4 inhibitors, meaning they can actually boost protease inhibitors, for example. It's like ritonavir [Norvir] boosting. That's actually very interesting as well.

I guess you're thinking about proceeding with human pilot studies, too. How is that going to happen?

I've already spoken with officials at the NIH [U.S. National Institutes of Health] as well, and to physicians who specialize in viral eradication. They're trying everything but the kitchen sink. The fact that this drug is already approved and under controlled conditions, we're planning to do a carefully designed clinical study. We want to do this in monkeys first as a proof-of-concept, but I think there's enough interest among some of the physicians I've talked to to perhaps do a small pilot study and see whether indeed this works the way it's supposed to. This is all very new stuff. So we're gearing up toward that and we hope that we will get our protocol approved so we can actually try it in humans.

It's also a question of getting some funding for that study, but it's a small number of patients because it's a high risk, high return and I don't think the drug on its own is going to be enough. We need to basically find patients who are already virus suppressed on HAART and add on this molecule for a few months and eventually take off the other medication and see what happens; see if the virus gets reactivated or reactivation is delayed. You have to select very carefully the population of patients that you're going to use for the study; they shouldn't be very sick and we have to be careful, because resistance could be an issue, especially in patients who've had HIV for a long time. So you don't want to withdraw treatment unnecessarily. The patients have to be monitored very carefully. We also have to develop better methods for detecting virus at very low levels. It's something that we can do now with the technology available for that purpose. That's why I wanted to do this in monkeys first, but as I said, some of my colleagues indeed would like to go straight into humans.

Will the funding come from the NIH or from any of the companies like Pfizer? Are they interested in this kind of indication?

I cannot talk, because I have a CDA [confidential disclosure agreement] with the company. I cannot discuss which company. All I can tell you is I'm working with a company at this stage, trying to look at better drugs that would have lower toxicity and be safer to use specifically for this purpose. I don't know whether they have funds for this study. We have other resources and for a pilot study it will not be costly.

This transcript has been edited for clarity.