Ibalizumab: First HIV Drug to Get Orphan Drug Status for Salvage Patients

Shares of TaiMed Biologics Inc, which manufactures drugs to treat AIDS, soared 12.93 percent yesterday after its new TMB-355 drug for intravenous injection was granted orphan drug status in the US.

The company’s shares closed at NT$151.2 yesterday, outperforming the over-the-counter benchmark index, which ended up 0.56 percent.

The granting of orphan status could shorten the time it takes for TMB-355 to enter the US market, TaiMed financial controller Jack Chen said over the telephone yesterday.

“By getting orphan status, we are able to negotiate with the US Food and Drug Administration to see if we can waive the phase-three clinical trials for the drug, or conduct them on a smaller scale,” Chen said.

An orphan drug is one that satisfies an unfilled medical need for a specific group of people numbering less than 200,000, TaiMed said, adding that as a result, clinical trials for such drugs do not require as many patients as those for other pharmaceuticals.

http://www.taipeitimes.com/News/biz/archives/2014/10/23/2003602680

FDA approved Jak inhibitors and their potential use in HIV - Interview with Dr Raymond Schinazi

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.

New HIV, Hepatitis C and TB Medications in the Research Pipeline' Report from TAG and I'Base

I highly recommend this excellent pipeline report for an update of what drugs are in the development pipeline for HIV, Hepatitis C and TBÑ

2012 Pipeline Report

New HIV Drugs in the Pipeline - 2012

Gilead has completed and released 48-week data from ongoing phase 3 studies of a four-drug fixed dose combination (elvitegravir, cobicistat, tenofovir, and FTC- called QUAD), as it has with studies of the integrase inhibitor elvitegravir and the pharmacokinetic booster cobicistat.  QUAD  will likely be approved for treatment naive patients after August this year.

 Results from phase 3 studies of the integrase inhibitor dolutegravir (formerly S/GSK-572) have been submitted to the FDA. This drug may be approved later this year for treatment naive and experienced patients. This drug is now available via expanded access to patients who have developed resistance to raltegravir. As with any other drug, it has to be combined with at least one fully active medication and a background therapy for it to control HIV.  But some patients do not have another medication to use with dolutegravir, so they will have to wait for other new drugs to be available via expanded access or single patient access programs in the future. Another HIV medication with a new mechanism of action may not be approved in the next 2.5- 3 years.

Phase 2 studies continue or are expected for an attachment inhibitor (BMS-663068) that may work for HIV mutidrug resistant virus, and a CCR5 inhibitor (cenicriviroc, formerly TBR-652) for treatment naive patients. BMS also has a continued with the developement of Festinavir , a nucleoside reverse transcriptase inhibitor that is active against HIV resistant to both abacavir and tenofovir, making the drug a candidate for people with multi-drug resistant (MDR) strains of the virus. 

Phase 2 results for the attachment inhibitor ibalizumab were presented last September at the ICAAC conference.   Ibalizumab's manufacturer, Taimed Biologics, is also testing a subcutaneous formulation instead of the intraveneous one used up to now is their studies.  Both formulations are dosed every two weeks.  As other small biotech companies (Tobira, Avexa, and Progenics), Taimed is currently looking for financial partners to proceed to phase 3 studies. 

Phase 2 results for the NNRTI lersivirine (previously known as UK-453061) in treatment-naive patients were presented at the International AIDS Society's (IAS) Conference in Rome last summer.  GSK-ViiV is exploring this and other drugs as part of a long acting ARV regimen provided via subcutaneous injection (no oral drugs) every week or two weeks. This will revolutionize HIV treatment, in my opinion.

Three compounds had their development discontinued: vicriviroc (a CCR5 inhibitor), GSK-761 (an NNRTI), and bevirimat (a maturation inhibitor).

The drugs that may work for multidrug resistant HIV are ibalizumab, BMS-663068, dolutegravir,  and potentially lersivirine and apricitabine. However, only dolutegravir is now available via expanded access. As a salvage therapy research advocate, I am looking forward to hearing from BMS, Taimed, Progenics about their upcoming phase 3 studies and future expanded access programs. Stay tuned for an upcoming article in Treatment Issues  about salvage therapy access for the dwindling but vulnerable population of patients with extensive HIV multi-drug resistance.

As a side note, some preliminary cure related studies have started enrolling:
HIV Cure Related Studies 

Is There a Future for HIV-Infected Patients in "Deep Salvage"?

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By Nelson Vergel, B.S.Ch.E., M.B.A.

May 3, 2011

"Only patients who do not take their medications as prescribed have multidrug resistance."
"Deep salvage patients no longer exist. The ones in that situation are already dead or have responded to the latest HIV antiretrovirals."
"Even if we give expanded access to multiple investigational agents to patients in salvage therapy, it will be a waste since most of these patients have adherence problems."
"It is too expensive and cumbersome for my clinic to provide expanded access."
"My institution no longer participates in expanded access due to costs and manpower problems."
These are statements that I have heard in different meetings that I have attended in the recent past to discuss access and research issues in HIV. Some of these statements are very hard for me to hear, since I am one of these "difficult patients" who have "failed" most commercially available medications -- despite the fact that I, like many of my peers, am certainly not a patient who lacks perfect adherence.
Most of us built resistance as we joined study after study that exposed us to functional monotherapy. In fact, I consider many of us who have been struggling with multiple drug resistance to be wounded soldiers from a time when we were recruited into studies we joined out of desperation to access a new drug. Even if we seem invisible due to our lower numbers, we are still here -- and we absolutely hate to be discounted as disposable in the current era of largely successful HIV treatment.
It is my opinion, and that of several clinicians that I have worked with, that it is the pharmaceutical industry's duty to provide access to multiple investigational drugs so that so-called "salvage patients," such as myself, can finally construct a regimen that may help us join the population of virologically controlled patients.
We all know that the management of resistant HIV disease has improved dramatically with the approval of a number of highly effective antiretroviral drugs, including darunavir (TMC114, Prezista), etravirine (TMC125, Intelence), maraviroc (Selzentry, Celsentri) and raltegravir (Isentress). Among this recent generation of antiretroviral drugs, perhaps the most promising is raltegravir, the first clinically available inhibitor of HIV integrase. When used in combination with other active drugs, raltegravir has proven to be very potent, well tolerated and highly effective. In phase 2 and 3 clinical trials, the vast majority of patients who were able to combine raltegravir with at least one other active drug achieved durable viral suppression. (Comparable efficacy has been seen in patients who received darunavir, etravirine or maraviroc with at least one other effective agent.)
Despite the impressive effectiveness of these drugs in clinical trials, a subset of patients has exhibited virologic failure while on these drugs. Most failures likely occurred because of the inability to construct a regimen that contained two to three fully effective agents. Adverse events, drug-drug interactions and non-adherence also likely contributed to the inability of some patients on these drugs to achieve durable viral suppression. As a consequence of these factors, the failure rates in the recent phase 3 studies -- DUET (etravirine and darunavir), MOTIVATE (maraviroc) and BENCHMRK (raltegravir) -- were in the 27% to 40% range.
The picture gets less encouraging when looking at longer-term data. As shown in the following figure, a longer-term study generated from following patients using raltegravir for 144 weeks showed failure rates of 40% to 56% even in patients with one or more active agents in their background therapy.

But I guess these patients disappear into the dark, since many physicians do not seem to know who they are. It is assumed that many of the patients who failed these recent studies were subsequently unable to construct a suppressive regimen, although the long-term outcomes of those failing these clinical trials are unknown.
The prevalence of multi-regimen failure in clinical practice is also unknown. Steven Deeks, M.D., and colleagues at the University of California San Francisco/San Francisco General Hospital have an ongoing observational cohort of patients who have developed drug-resistant HIV (the SCOPE cohort). Most of these patients have been able to construct a fully suppressive regimen and are currently doing well clinically.
However, of the original 300 SCOPE patients, approximately 40 now have evidence of having failed all six therapeutic drug classes. These 40 patients have a genotypic sensitivity score (GSS) of either zero or one, and they have no clear options for suppressing HIV replication. Many have advanced disease (with a CD4+ cell count of less than 100 cells/mm³) and hence may not be able to "wait" for the development and approval of multiple new options.
In an informal online survey I made with the help of a team of investigators and activists, which was presented in a meeting with the U.S. Food and Drug Administration (FDA), 83 physicians around the country reported having a total of 252 patients with a GSS of zero or one.

The most surprising finding was the wide geographical distribution of these patients. Physicians from 47 U.S. cities and towns reported treating them. Although the larger cities had the most patients with a low GSS, many patients lived in small towns that are far from research sites or large practices that are more equipped to handle the needed paperwork to apply for expanded access or single-patient emergency drug access programs.

Much of the expanded access program documentation and nurse/physician time is not reimbursable or paid for by studies, so most doctors participating in these programs are doing so from the goodness of their hearts. Many large medical schools and clinics have stopped providing expanded access help to their patients entirely.
The following chart outlines some of the reasons reported by survey participants for not applying for early access to investigational drugs for their patients. The most common reason was that they simply did not have the administrative support they needed to handle the required paperwork. Many also expressed frustration with an application process they felt was too complex.

Given that patients who are unable to construct a background regimen often fail therapy, the FDA and other interested groups have advocated that future clinical trials only enroll patients whose background regimen has a GSS or phenotypic susceptibility score greater than or equal to one. Although this is an ethically sound recommendation, one unfortunate consequence is that those patients who have now progressed to multi-regimen failure won't be able to access experimental drugs via clinical trials.
Unfortunately, the HIV drug pipeline in 2011 is a lot more limited than it has been in the past due to many factors, including the relatively small size of the U.S. market, drug development costs, and the difficulty in finding treatment-experienced patients with one or more active agents in their background therapy. Some drugs have already been abandoned due to these issues, as shown by this table.

Thankfully, the FDA has proposed a new trial design concept that will facilitate the development of medications for treatment-experienced patients, which may encourage pharmaceutical companies not to abandon HIV drug development. For more information about this novel trial design concept, refer to a presentation given by Jeffrey Murray, M.D., M.P.H., from the FDA at a recent meeting sponsored by the Forum for Collaborative HIV Research.
However, even with these efforts, the possibility of constructing a regimen with three active agents for the salvage population within the next four years is low, which will diminish the chances for survival in those with lower CD4+ cell counts.
I've laid out a grim scenario in this blog post, but in my next post, I'll discuss a potential silver lining: a program in the works that I hope will greatly expand options for deep salvage patients in need of access to investigational agents.

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