Showing posts with label new HIV drugs. Show all posts
Showing posts with label new HIV drugs. Show all posts

Thursday, March 14, 2013

New HIV Drugs and Formulations in the Near Future (CROI 2013 Presentation)


All of the presentations in this section were great.

The one on new drugs is contained in the last set of slides (blue slides at 1:22:46)


http://webcasts.retroconference.org/console/player/19437?mediaType=podiumVideo


For individual reports on each drug (Thanks to Natap.org):


NEW HIV DRUGS at CROI

Monday, December 17, 2012

Six Promising HIV Drugs in the Pipeline (2013-2014)





By Warren Tong
December 5, 2012

Introduction
What new HIV medications do we have to look forward to over the next few years? How will these newer drugs improve upon the older ones? To shed some light on these questions, Roy Gulick, M.D., provided an overview at ID Week 2012 of drugs in development.
Since the first HIV medication, zidovudine (AZT, Retrovir), was approved in 1987, 26 other antiretrovirals have been made available in the U.S. for treating HIV -- a history that Gulick recapped in song during this conference. Our best regimens today are potent, convenient and relatively non-toxic.
However, according to Gulick, there is potential to make medications even better than those we have today. Newer drugs should build upon some of these aspects, he said:
  • Improve convenience (reduce dosage frequency, less than once a day).
  • Improve tolerability and reduce toxicity (even the best drugs today still have some of these issues).
  • Penetrate reservoirs more effectively (such as the genital tract and central nervous system).
  • Exploit new targets, thereby improving activity (particularly against drug-resistant viruses).
  • Improve formulation.
The list of drugs in the pipeline continues to be full of antiretroviral agents, whether they are in early development or undergoing clinical trials.
Gulick highlighted six of the most promising drugs.

GS-7340 (Also Known as Tenofovir Alafenamide, or TAF)
GS-7340 is an investigational nucleoside agent that is a prodrug of the approved formulation of tenofovir (TFV, Viread). A prodrug is a medication that, when metabolized in the blood, breaks down into the active form of the compound. The NRTI sold under the brand name Viread is actually tenofovir disoproxil fumarate (TDF), a prodrug that breaks down into tenofovir.
GS-7340's antiretroviral activity was first presented in a study by Martin Markowitz, M.D., and others at CROI 2011. In a small, 14-day study, Markowitz and his team found that GS-7340 performed slightly better than the "old" TDF, with greater decreases in HIV RNA at lower dosages (GS-7340 at 50 or 150 mg vs. TDF at 300 mg).
These findings were further supported by study results from Peter Ruane, M.D., and others at CROI 2012. Ruane and his team compared GS-7340 (at dosages of 8, 25 and 40 mg) with TDF (at 300 mg) in 38 treatment-naive patients over 10 days of monotherapy. GS-7340 again performed better than TDF, showing 0.76, 0.94 and 1.08 log reductions in HIV RNA, respectively, while TDF only showed a 0.48 log reduction in HIV RNA. The findings were statistically significant for the 25-mg (P = .017) and 40-mg (P = .01) dosages.
Ruane and his group also found that the plasma concentrations of tenofovir, when the prodrugs were metabolized, were 10 to 100 times higher for TDF than for any of the three dosages of GS-7340. This finding suggests that, because GS-7340 delivers less compound to target tissues, it could reduce toxicity levels in the organs, Gulick said.
On the other hand, when comparing intracellular concentrations of tenofovir in peripheral mononuclear cells like lymphocytes (which is where we want the drugs to be), GS-7340 achieved up to 20 times higher levels than TDF, Gulick noted.
In both of these studies, GS-7340 was generally well tolerated and no serious adverse events were reported.
A third study of GS-7340 was presented at ICAAC 2012. It found that GS-7340 had high potency against 26 HIV-1 isolates representing 7 subtypes. The drug also showed high potency against three HIV-2 isolates. In addition, GS-7340 maintained its viral potency longer than TDF, showing its better stability.
Further GS-7340 studies are in progress. Particularly because of its low dosage and high potency, it can be readily co-formulated with other agents.
Gulick pointed out two studies exploring such coforumulations. The first study will compound GS-7340 with emtricitabine (FTC, Emtriva) plus elvitegravir (EVG) plus cobicistat, and compare that to elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild). The second study will compound GS-7340 with emtricitabine, darunavir (Prezista) and cobistat (which would be the first one-pill, once-a-day protease inhibitor-based regimen), and compare that to tenofovir/emtricitabine (Truvada) plus darunavir plus cobicistat.

Dolutegravir (DTG)
Of the six highlighted compounds, Gulick stated that dolutegravir is the furthest along in development. Dolutegravir is an investigational integrase inhibitor, but it has distinguished itself from the two approved integrase inhibitors, raltegravir (Isentress) and elvitegravir.
Dolutegravir has a long half-life of 15 hours, indicating it can be taken once a day. Gulick emphasized that it does not require pharmacokinetic boosting. He noted that resistance does occur, but that dolutegravir showed activity against raltegravir- and elvitegraivr-resistant viral strains.
Its antiviral potency was shown in a phase-2a study by Sherene Min, M.D., and others. In 28 treatment-naive patients receiving either 2, 10 or 50 mg of dolutegravir, there was an average of a 1.51 to 2.46 log reduction in viral load after only 10 days of once-daily dosing. Seven of the 10 patients receiving 50 mg dosages achieved a viral load less than 50 copies/mL. Min and her team reported low pharmacokinetic variability and good short-term tolerability (the most common side effects were diarrhea, fatigue, and headache; adverse events were mild to moderate in severity).
According to Gulick, phase-3 results are complete and will be submitted to the U.S. Food and Drug Administration by the end of the year.
One of the phase-3 studies, known as SPRING 2, found dolutegravir to be non-inferior to raltegravir. The study followed 827 treatment-naive patients with a viral load above 1,000 copies/mL over 48 weeks. They were given either 50 mg of dolutegravir or 400 mg of raltegravir. Both groups were successful at achieving viral loads below 50 copies/mL (88% for dolutegravir and 85% for raltegravir). Both drugs were also very well tolerated, with only 2% in each group having to discontinue treatment because of adverse events.
Furthermore, a dolutegravir-based regimen consisting of abacavir/lamivudine (Epzicom, Kivexa) plus dolutegravir was actually found to be superior to tenofovir/emtricitabine plus efavirenz (Sustiva, Stocrin), according to the results of a companion phase-3 study by Sharon Walmsley, M.D., and others. In 822 treatment-naive patients studied over 48 weeks, 88% of the dolutegravir group achieved a viral load below 50 copies/mL, compared to 81% of the efavirenz group.
Gulick pointed out that the difference was because of tolerability: 10% of the efavirenz group discontinued treatment because of adverse events, compared to just 2% of the dolutegravir group. He commented that this would mark the first real challenger to efavirenz's long-held dominance in treatment-naive studies with a 48-week primary endpoint.
In terms of renal safety, the study found dolutegravir did interfere with tubular secretion of creatinine. However, Gulick noted, the increase in creatinine was only about .1 to .15 mg/dL, and occurred only within the first two weeks after starting dolutegravir, then stabilized over the rest of the 48-week study. As the Walmsley study noted, dolutegravir does not affect actual glomerular filtration rate.
In terms of resistance, dolutegravir appears to have a higher barrier to resistance than the other integrase inhibitors. In the Walmsley study, among both the dolutegravir and efavirenz groups, only 4% experienced virologic failure (18 and 17 individuals, respectively). Of the nine in each group that had genotypic test results available, "You see no nucleoside and no integrase mutations in the dolutegravir group. And as you would expect in the efavirenz [regimen], there were some nucleoside and non-nucleoside mutations detected," Gulick stated.
Because dolutegravir showed activity against elvitegraivr- and raltegravir-resistant viral strains, as shown in a study by Masanori Kobayashi and others, Joseph Eron, M.D., and others studied the use of dolutegravir for patients who had developed resistance to raltegravir. Their pilot study, known as VIKING, followed 51 patients with three or more class resistances, including demonstration of raltegravir mutations. The patients were given 50 mg of dolutegravir, either once or twice a day, for 10 days. A virologic response was defined as either a viral load below 400 copies/mL or a 0.7 log reduction. As Gulick explained, "The best responses were in the twice-a-day group. Whether you looked at all patients, those with the specific Q148 or other mutations, you can see response rates, over a short 10 days of therapy, exceeding 90%."
The VIKING study went on to follow the patients over 24 weeks. After the initial two weeks, the patients added an optimized background regimen. These follow-up results were presented by Vincent Soriano, M.D., Ph.D., at the 2011 European AIDS Conference. Soriano and his team found that by the end of the 24-week period, 41% of the once-a-day group and 75% of the twice-a-day group were able to re-suppress their viral load below 50 copies/mL.
Further studies of dolutegravir in the setting of other integrase inhibitor resistance are ongoing.

S/GSK-1265744 (or simply "744")
S/GSK-1265744 is an integrase inhibitor, similar to dolutegravir. Results from two studies presented at ICAAC 2012 found that 744 had high potency and an exceedingly long half-life. When given orally at once-daily doses of 30 mg, patients showed a median 2.6 log reduction in viral load.
More impressive, when using nanotechnology to formulate 744 to be injected subcutaneously or intramuscularly, a single dose showed a half-life between 21 and 50 days.
Remarkably, after a single dose, patients still had detectable levels of 744 up to 48 weeks after injection.
Similar to dolutegravir, 744 seems to have a high barrier to drug resistance. According to Gulick, using site-directed molecular clones (molecules created with specific mutations) associated with integrase inhibitor resistance, these mutations showed high levels of resistance to raltegravir and elvitegravir, but remained susceptible to 744 and dolutegravir.
In terms of safety, there were some injection site reactions and nodules associated with subcutaneous dosing. But conceivably, 744 could be taken as infrequently as every three months for treatment, or even as PrEP (pre-exposure prophylaxis). Research is ongoing.

HIV Entry Inhibitors
HIV entry inhibitors block HIV at the point at which they attach to CD4 cells. Many of the other classes of drugs, including protease inhibitors, NRTIs and NNRTIs, fight HIV after it has infected a CD4 cell.
Among the entry inhibitors, there are presently three sub-classes. We already have approved drugs in the first two sub-classes: CCR5 antagonists and fusion inhibitors. In the CCR5 antagonist sub-class, we already have maraviroc (Selzentry, Celsentri), and a new drug called cenicriviroc is being investigated. The fusion inhibitor class has long featured only enfuvirtide (Fuzeon), but a new drug called albuvirtide is being studied.
The third sub-class is an investigational one: CD4 attachment inhibitors. These new drugs are being developed to either bind at the location of HIV's gp120 protein (such as BMS-663068) oron the CD4 receptor itself (such as ibalizumab, a once- or twice-a-day drug that's still under investigation for both treatment and prevention).
Gulick offered a closer look at a few of these drugs in his overview.

Cenicriviroc (CVC)
Cenicriviroc is an investigational CCR5 antagonist. Not only does it antagonize CCR5 binding, it also antagonizes CCR2 binding. CCR2 is a receptor that sits on the surface of macrophages and may be involved in inflammation.
Cenicriviroc showed potent antiretroviral activity in a small study by Jacob Lalezari, M.D., and others. They followed treatment-experienced patients who had not been on treatment for at least six weeks, had a CD4+ cell count above 250 and a viral load above 5,000 copies/mL. They were randomized to receive either 25, 50, 75, 100 or 150 mg of once-daily cenicriviroc. At the highest doses, after 10 days, patients showed a 1.5 log reduction in viral load.
An update on the follow-up study was discussed by David Martin, M.D., at CROI 2012. In Martin et al's phase-2b study, they randomized 150 treatment-naive patients into three groups to receive tenofovir/emtricitabine with either cenicriviroc (at 100 or 200 mg) or efavirenz. Cenicriviroc was administered using a new, 50-mg formulation. In preliminary data from 18 patients, cenicriviroc was found to be well-absorbed and within the expected therapeutic range of potency. Further study will assess the safety, efficacy and effect of CCR2 inhibition on inflammatory biomarkers.

Albuvirtide
The only approved fusion inhibitor, enfuvirtide, offers a lot of activity against HIV, but the obvious downside is that it requires twice-daily injections. Albuvirtide, on the other hand, is an investigational fusion inhibitor that when given intravenously has a long average half-life of 11 days, warranting weekly dosing.
Albuvirtide has a similar design to enfuvirtide. It is a peptide that is an analogue of gp41, one of the envelope proteins on HIV's surface, and thereby blocks HIV through CD4 membrane fusion.
Two proof-of-concept studies by Dong Xie and others were presented at ICAAC 2012. In the first study, albuvirtide was given to 54 treatment-naive patients in a single dose; doses ranged from 20 to 640 mg. They found that albuvirtide's half-life ranged between 10 and 13 days, and that the drug suppressed plasma viremia for between 6 and 10 days. Albuvirtide was generally well tolerated, with no injection-site reactions and no serious adverse events.
In the second study, albuvirtide was given to 12 treatment-naive patients in multiple doses of either 160 or 320 mg. Doses were given on days 1, 2, 3, 8 and 15. The participants averaged viral load decreases of 0.68 log copies/mL (at 160 mg) and 1.05 log copies/mL (at 320 mg). Similar to the first study, there were no injection-site reactions and no serious adverse events. No anti-albuvirtide antibodies were detected in patients for up to 42 days.

BMS-663068 (a.k.a. BMS-068)
BMS-068 is an HIV attachment inhibitor. It is an oral prodrug that breaks down into the active compound BMS-626529 (a.k.a. BMS-529). It inhibits CD4 binding by specifically binding to gp120, one of HIV's envelope proteins that binds to CD4 cells. Gulick stated BMS-068 could be taken once or twice a day without boosting, but noted, "There is decreased baseline susceptibility in some patients due to envelope polymorphisms."
BMS-068 taken over 8 days with or without ritonavir (Norvir) resulted in substantial declines in plasma HIV RNA levels and was generally well tolerated, according to a study by Richard Nettles, M.D., and others. The study followed 50 patients with a CD4+ cell count above 200 cells/mL and a viral load above 5,000 copies/mL. They were either treatment-naive or not taking any treatment. The median change in viral load ranged from a 1.21 to a 1.73 log reduction, demonstrating that CD4 attachment inhibition can be quite potent and effective.
In terms of resistance, a study presented by Neelanjana Ray, M.D., at CROI 2012, found little resistance after the eight days of monotherapy. Ray and his team analyzed the changes in phenotypic susceptibility and known attachment inhibitor resistance substitutions that may have occurred during the Nettles study. Of the 48 patients that completed the study, 42 had at least a 1 log drop in viral load, showing that BMS-068 was effective. However, the other six (about 12%) had no virologic response, even though their baseline IC50 (a measure of the effectiveness of a compound in inhibiting a biochemical function) levels were quite high.
"When they took a close look and they sequenced gp160, which is broken down into gp120, they showed that a mutation (M426L) was associated with resistance," explained Gulick. "You can see that in patients with virologic response, very few (only 6%) have this mutation, whereas in those without virologic response, 5 of the 6 had this mutation. So it looks like this will be important in screening for activity of this compound as its development moves forward."

New Fixed-Dose Combination and Antiretroviral Formulations
Gulick pointed out three one-pill, once-a-day formulations being developed:
  • GS-7340/FTC/elvitegravir/cobicistat.
  • GS-7340/FTC/darunavir/cobicistat.
  • Abacavir/lamivudine (3TC, Epivir)/dolutegravir.
In addition, three other in-development formulations that Gulick mentioned were:
  • Lopinavir/ritonavir/lamivudine.
  • Atazanavir (Reyataz)/cobicistat and darunavir/cobicistat (both in clinical trials).
  • Rilpivirine long-acting (RPV-LA).
Regarding the last drug in those lists, a small pilot study presented at CROI 2012 found that RPV-LA could potentially be given once a month in its long-acting nano-formation. It would likely need to be paired with other drugs, but research is ongoing for its use in treatment and prevention.
Warren Tong is the research editor for TheBody.com and TheBodyPRO.com.
Copyright © 2012 Remedy Health Media, LLC. All rights reserved.

http://www.thebodypro.com/content/69959/six-promising-hiv-drugs-in-the-pipeline.html


 This article missed the drug ibalizumab:

 TMB-355(Ibalizumab) is a humanized monoclonal antibody (mAb) and a member of an emerging class of HIV therapies known as viral-entry inhibitors. This drug candidate is distinct from other entry inhibitors in that it binds to the CD4 molecule, the primary receptor for HIV infection, thereby interfering with the penetration of the virus into the cell. It is the first entry-blocking humanized mAb to treat HIV/AIDS. TMB-355 caught the attention of the scientific community in February 2003, when results from the phase-1, single-dose clinical trial showed a transient but clinically significant reduction in the patients’ viral load. Moreover, it was well tolerated with no evidence of adverse effects on CD4 T-cells of treated subjects unlike the majority of approved drugs for HIV. The U.S. FDA granted TMB-355 fast track status in October 2003. The phase-2a clinical trial was successfully completed in 2006, with the results showing a clean safety profile and clear antiviral activity (10-fold reduction in viral load).  The Phase-2b clinical trial was also successfully completed in 2011. TaiMed Biologics is concurrently developing a subcutaneous injection dosage form and a phase 1 human pharmacokinetics bridging study is completed in 2012. Currently, TMB is developing a phase I/II study for HIV-negative and new HIV-positive subjects to begin by the end of 2012.

Wednesday, September 19, 2012

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.

Friday, June 15, 2012

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 

Thursday, July 10, 2008

The Coming Crisis in HIV Drug Development

Excellent article by Paul Dalton

Project Inform
The Coming Crisis in HIV Drug Development
By Paul Dalton

June 16, 2008

The last few years have seen tremendous progress in treating people with advanced and drug-resistant HIV. Four powerful drugs became available that either overcame drug resistance (Prezista [darunavir, TMC-114], Intelence [etravirine, TMC-125]) or were from entirely new classes [Selzentry (maraviroc), Isentress (raltegravir)].

This marked an important and unique moment in HIV drug development. Never before have so many new and effective drugs come out so close together. People with extensive experience taking HIV drugs have been able to put together powerful regimens with two or more fully active agents -- often for the first time.

Project Inform took pains to highlight both the tremendous promise of these new drugs as well as the importance of using them correctly -- emphasizing that this moment, or anything resembling it, is unlikely to recur. Our message was clear: 'Seize this opportunity, use the new drugs carefully, and don't waste this once-in-a-lifetime chance'.

As good as some of these newer drugs have looked in studies, there are emerging signs of trouble in the real world. Dr. Steven Deeks, a prominent HIV physician and researcher says, "Although the current generation of drugs are generally doing great, many patients are not responding in a durable manner. We are now following about 25 individuals who have failed all six drug classes. The key now is to design regimens to maintain immunologic and clinical stability while we wait for more drugs. I am concerned, however, as it will likely be a few years before we have another shot at getting the virus under control. We desperately need a second generation integrase inhibitor that works against viruses resistant to raltegravir."

Dr. Deeks' experience is far from typical. He follows many of the most treatment experienced people in the San Francisco Bay Area, many of whom have been on therapy since 1987. Although not typical, his experiences have been reported elsewhere, if in smaller numbers.

This suggests a burgeoning problem of people beginning to run out of treatment options, as has happened a couple of times during the epidemic. Project Inform is concerned that the most vulnerable people living with HIV will be left with few or no viable treatment options, possibly for many years.

One of the unintended effects of the recent successes in drug development is that fewer people are available for studies of experimental drugs aimed at treatment experienced folks. We saw this coming and have been counseling drug companies and the Food and Drug Administration (FDA) that the era of 'TORO-like' studies was coming to a close. These studies give volunteers optimized background therapy (the best combination of HIV drugs chosen with resistance test results) with either the experimental drug or a placebo. The design allows regulators, scientists and activists to clearly see the benefit of the new drug. (Some call these studies 'TORO-like' after those that led to the approval of Fuzeon [enfuvirtide, T20]).

This contrasts with how studies of first line treatment are done. When studying HIV drugs as first line, the basic model is head-to-head non-inferiority studies, which are designed to tease out the relative contribution of the entire regimens rather than the individual drugs. (Non-inferiority means that one drug or regimen is equivalent or 'close enough' to another.)

The FDA has allowed non-inferiority studies for drugs being studied as first line, but has insisted on placebo controlled superiority studies for treatment experienced studies. This made a good deal of sense when there were many people signing up for these studies. The situation is now quite different.

While there aren't enough people signing up for these kinds of studies, there's still a sizeable need for studying new HIV drugs. This, combined with the thin drug pipeline and the current difficulty recruiting for studies, may add up to real trouble down the line.

In meetings with many drug companies Project Inform has warned of this impending problem and recommended that they adopt new ways of studying their drugs. The reaction has been mixed. While some companies have been quite open to new ideas, it's fair to say that most would prefer to stick with models that have proven successful.

We have struggled to argue -- to the companies and the FDA -- that ways of studying and developing drugs are both necessary and possible. Gilead Sciences is one of the first to grapple with this. When it came time to do large, pivotal studies of their experimental integrase inhibitor, elvitegravir, there simply were not enough people in the US to enroll a typical study for treatment experienced people. Project Inform had warned Gilead, and others, of this eventuality and argued for studies that would more closely resemble the head-to-head, non-inferiority studies used for studying first-line drugs.

Over time Gilead came to agree that this was the way forward and submitted such a plan to the FDA. The FDA eventually allowed Gilead to move forward with this study design for elvitegravir. This is a great victory for people living with HIV. There is a great need for new treatments to be developed and for the FDA and companies to think and act creatively to ensure this happens.




An Overview of the Current State of HIV Drug Development
The Industry
As a whole, pharma has done a tremendous job developing HIV drugs. However, many visible signs are showing their fading commitment to HIV. Fewer new companies are getting into HIV, and some well established ones are either cutting back or eliminating their drug development plans. The marketplace for HIV drugs is both crowded and competitive. The scientific hurdles for developing new HIV drugs have also grown more difficult, making it a less attractive market for companies.

The FDA
The FDA is responsible for ensuring that drugs are safe and effective before they become available outside clinical studies. Recent media stories that focused on drug safety, particularly on Vioxx and Heparin, have created a somewhat fearful climate inside the FDA where new ideas are met skeptically. Their recent decision to green light elvitegravir's development shows that at least its antiviral division is open to creative drug development plans.

The Current Pipeline
All in all, the pipeline is both thin and unimpressive. There are a few 'me too' drugs (slight changes in existing drugs) which are helpful but not game changing. A few novel compounds may prove promising down the line, but they're struggling right now, due to either study results or in one case the company being bought by a company that doesn't want to work in HIV.

As for those drugs in human studies, the closest to approval is rilpivarine (TMC-278), an NNRTI for first line treatment being studied against Sustiva. Vicriviroc, Schering's CCR5 drug, continues to flounder but is still viable. Bevirimat, a maturation inhibitor from Panacos, has been hamstrung by formulation problems. Other drugs we are following are Pharmasset's racivir, and Avexa's apricitabine.

The Bottom Line
The past two years have been a boon to people with extensive treatment experience. Four successful new drugs, including two new classes, have meant most people can put together powerful, effective and tolerable regimens, even if they've never been able to get to undectable before. However, this period is now over, and we're experiencing a major downturn in the number of promising drugs in the pipeline.

This reinforces the importance of using the current crop of new drugs correctly. Your best chance at getting to and staying undetectable is to start a regimen with at least two and hopefully three fully active drugs. If you're able to do this and get your HIV level to undetectable, good adherence is the best way of keeping it there.

This also points to the need for treatment activists, like Project Inform, to continue to work with the companies, scientists and regulators to ensure that new drugs are developed.
Lastly, this situation points toward the need for a cure. It is only going to become more difficult to keep the companies, their researchers and the general public interested in HIV drugs. There's a growing sense that HIV is not that much of a problem anymore, at least not in wealthy countries.

The only real solution is a cure. While some may discount its possibility, we do not. Many promising approaches are under study, as well as a resurgence in community activism aimed at cure research. A conscientious program mounted by academia, industry, government and community is necessary to reach this goal.

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