As part of my
work as a cure and salvage treatment activist, I am constantly searching for
treatment options that could serve two purposes: existing medications that
could help patients with multidrug resistance and at the same time be used as
an approach to cure HIV. Since my non
profit (Program for Wellness Restoration) has a very small budget for me to
attend conferences, I rely on summaries that Jules Levin and his group
(NATAP.org) publishes after he attends conferences. I am glad Jules can serve as eyes and ears for
those of us unable to attend so may important scientific meetings.
Rarely I come
across information about a drug that is already available and which can treat
HIV and hopefully also help decrease its reservoirs. While reading
one of NATAP's great summaries about the recently held International Workshop on HIV and Hepatitis in Sitges (June
5-9) I came across a completely new approach that could meet the two goals.
One of the abstracts presented by Dr Raymond F Schinazi 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 (to be approved
soon by the FDA for myeleofibrosis) and Jakafi (already approved by the FDA
for rheumatoid arthritis) demonstrated excellent inhibition of HIV replication
at very low concentrations in vitro as well as against replication of a SHIV
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 a 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.
I contacted Dr Schinazi and he was happy to speak about his findings.
Raymond F. Schinazi, PhD, DSc 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 7 books, and holds more than
100 U.S. patents. He is best known for his innovative and pioneering work on
FTC (emtriva), 3TC (lamivudine), d4T (stavudine), LdT (telbivudine), 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 the HIV-infected individuals take at least one of the
drugs he invented. Dr. Schinazi has served on the Presidential Commission on
AIDS and currently serves on the Board of Trustees of AMFAR. Due to his many
business accruements and notable academic accomplishments, Dr. Schinazi is
internationally recognized as one of the most influential persons in the life
science sector.
Nelson Vergel: Dr Schinazi,
thank you so much for taking the time to talk to us at TheBody.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.
Dr. Raymond Schinazi: 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.
Nelson Vergel: Well, I
have to say I’ve been positive for 27 years and that your work
has definitely made a difference in my life now that I know what you’ve done.
Dr. Raymond Schinazi: 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.
Nelson Vergel: Yes, of
course, you definitely have.
Dr. Raymond Schinazi: I’m also the founder of Pharmasset,
which is the company that has one of the best phase 3 HCV drug which was
sold in January 2012 for 11.4 billion dollars 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.
Nelson Vergel: it’s
amazing what you’ve done.
Could you please tell us about the abstract that you presented at the
recent International Workshop on HIV and
Hepatitis in Sitges about JAK inhibitors ?
Dr. Raymond Schinazi: There’s this pathway basically 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, and something we didn’t expect, inhibit
HIV application 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 down regulation the activation stage. In
activation stage, basically the normal cells that are surrounding the infected cells
becomes 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 ameanable 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 do 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 of HIV 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
mechanism associated with inflamation..
There
are lot 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. You know, 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, functional
cure, rather than an eradication cure. This is going to be very hard to do.
Even with a Berlin patient, 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.
Nelson Vergel: Yes
Dr. Raymond Schinazi: 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 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.
Nelson Vergel: I was
reading about a JAK inhibitor called Tofacitinib, a drug made by Pfizer that
got reviewed last month for a rheumatoid arthritis indication. I guess this
drug will probably be approved by the FDA soon.
Dr. Raymond Schinazi: We will know in August 2012.
Nelson Vergel: Yeah, it looks pretty good; low side effect
profile and BID dosing. I was looking at the in-vitro data here you presented
at the conference. The dose you used
ranged from 0.02 to 0.3 micro-molars. How does that dose translate if used in
humans? Also, are you proceeding with studies in humans?
Dr. Raymond Schinazi:
These drugs are given 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 inhibitors 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
nano-molar range. As mentioned, one is
already approved for chronic long term use in humans, which is important and
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 boosting. That’s actually very interesting as well.
Nelson Vergel: I guess you’re thinking about proceeding with
human pilot studies, too, and how is that going to happen?
Dr. Raymond Schinazi: I’ve
already spoken officials at NIH as well and to physicians who specialize in viral
eradication. They’re trying everything and 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 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 towards 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.
Nelson Vergel: Will the
funding come from the NIH or from any of the companies like Pfizer? Are
they interested in this kind of indication?
Dr. Raymond Schinazi: I
cannot talk because I’m a CDA 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.
Nelson Vergel: Yeah.
Let me give you a little background onmy work in HIV. I’m research advocate, as I told you I’m an
HIV positive patient myself and do a lot writings and educational programs and
work with different committee advisory boards for pharma and FDA and all that. As part of that work I’m part of what we call
an HIV cure working group. There’s maybe
eight or nine of us around the country meeting with researchers. We actually just organized a really good meeting to review different cure related
approaches. I have a summary I can actually email to you and we’re planning to
do another one of those review meetings maybe at the end of the year or so.
Also, actually I’m probably the number one advocate when it comes to multi-drug
resistance and salvage access because I myself have multi-drug resistance. So that’s
why I just jumped on when I read this paragraph in the summary, I jumped for my
own case because some of us even though there are lots of treatments out there
are on our last basic combination therapy and some of us may or may not
suppress the virus for many years. I’m
in a research study using a monoclonal antibody and maraviroc, which is
research drug. We’re still alive and
doing well and hopefully praying that our viral load doesn’t go up and we run
out of options because the pipeline is looking a lot drier nowadays. That’s why my work in the cure research and
also salvage therapy made me very interested in your work with JAK inhibitors,
so if you ever need any community advocacy, meaning letters of support for your
approach for the NIH, we do that. If you
ever need, for instance you’re doing a pilot study and have a very specific
target of patients that you want to enroll, we also spread the word really fast
in the community for – Actually I just finished a survey that I’m going to
publish in JAIDS on the risk tolerance of patients when it comes to cure
related studies because nobody really knows whether some patients are going to
altruistic enough to like you say, stop their meds after being suppressed and
what we have found is that 80% of patients, over 3,000 patients answered the
survey, are altruistic. They really want
the cure and are willing to take certain risks even though most of them are
doing well. There is a lot of, and I’m
glad we’re bridging right now, there is a lot of community support behind
approaches like the one you’re taking and I want you to be aware of that so if
you ever come across to a brick wall and there is a lot of that sometimes in
this.
Dr. Raymond Schinazi: Let
me tell you I didn’t get to where I am by accident, Nelson, I’ve had many brick
walls; I’ve smashed them to get to where I am today. I’m originally Italian; I think you’re
Italian, at least you sound Italian.
Nelson Vergel: I’m Venezuelan.
Dr. Raymond Schinazi: I would love to meet you face to
face, I’d like to know more about what you’re doing and if you can help
certainly I’ll keep you informed on what’s going on. We have a very strong group here at Emory
University. The nice thing about the
drug that I’m working with is that it’s already approved by the FDA, so it
should be a lot easier to test in humans.
Nelson Vergel: That would be great! Thanks again for taking
the time to give us an update on your very exciting work. I will reach out to you in the future to
check any progress in non-human primate and human studies.
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