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New Agents for the Treatment of HIV-1: Is the pipeline opening up?
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Summary from the 19th IAC 2012 in Washington DC
"New agents that work against resistant virus or by a novel mechanism are needed"----BMS-986001 (festinavir) in phase 2b, BMS-663068 in phase 2b, LEDGINs, CMX157, EFdA
Joe Eron, MD University of North Carolina
August 24, 2012
Introduction
In the US and other developed countries we have over 25 antiretroviral drugs and combinations to treat HIV-1. Initial therapy choices have excellent efficacy and over time we have learned to minimize though not eliminate adverse events and toxicity. An open question is, "Do we need more drugs and drug combinations?" The short answer is "yes". No initial therapy combination is close to perfect, evidenced by the multiple choice menu we have and the large number of different combinations that are used for initial therapy. Some initial combinations may be very convenient but have issues of tolerability or potency or drug-drug interactions. Other combinations may be less convenient, have troublesome or perhaps long-term or less predictable side effects. Emergence of resistance is clearly much less common with our potent initial therapies but there are still potential resistance consequences based on the initial choice our patients make based on our advice. Unfortunately we will also always need new agents for patients with resistance virus. Patients with multi-drug resistant virus are thankfully much less common but patients with 4-class resistance (NRTI, PI, NNRTI and integrase inhibitor(InSTI)) are present in low numbers in most large clinics and the numbers of these patients with ongoing viral replication are likely to slowly grow especially if we cannot pull together fully suppressive regimens. New agents that work against resistant virus or by a novel mechanism are needed and it is possible that we (the HIV community and payers) may be willing to pay more of a premium for these medications if they have no other role in therapy.
The recent International AIDS Conference in Washington DC, back in the US after many years, provided us with some exciting new data that will likely increase our choices for initial therapy and offer the potential for additional treatment options for more treatment experienced patients. Results of several large phase III trials for initial therapy were presented.
Dolutegravir
Dolutegravir is a potent, once-daily, integrase inhibitor that does not require pharmacological boosting in order to achieve therapeutic concentrations. At the dose chosen for development in treatment naïve patients (50 mg once daily) the trough (or Cmin) concentrations and many fold above the protein corrected IC90 of wild type virus. We have seen interesting phase II data in treatment naïve patients (Spring 1) where 10, 25 and 50 mg of DTG combined with 2NRTI (total N on DTG = 155) had similar efficacy to efavirenz based therapy over 48 [1] and 96 weeks. There were very few virologic failures in either arm and no emergence of InSTI resistance. Side effect profile looked promising though while the dose levels were blinded patients and providers were aware if they were on DTG-containing therapy. At IAC 2012 the first phase III results of a DTG-containing regimen were presented by Francois Raffi. The study, Spring 2, compared in a blinded fashion DTG 50 mg once daily with raltegravir 400 mg twice daily both given with the choice of either TDF/FTC or ABC/3TC. 48 week results were presented with the primary endpoint the FDA "snapshot" analysis. This is a non-inferiority study and the investigators chose to use a 10% non-inferiority margin (BTW - in my opinion given the very high success rates of initial combination therapy - a 10% non-inferiority margin should be the standard. Would you really want to consider a therapy that could be up to 12% worse than 85-90%? One could even argue that the non-inferiority standard should even be tighter than 10%). Four hundred and eleven participants were randomized and received at least one dose in each arm. The characteristics at baseline were balanced between arms. We should note that similar to more recent phase III studies in treatment naïve patients most of the participants were men (85%), most were white (85%) and the median baseline CD4 cell count was approximately 360 cells/mm3 - potentially reflecting earlier entry to care and earlier starts to therapy. As a consequence though only 28% of subjects had HIV RNA > 100,000 copies (though still over 200 participants - another advantage of tighter non-inferiority margins) and only 12.5% of subjects had CD4 cell counts less than 200 cells/mm3. Very advance patients were likely quite uncommon. Approximately 60% of patients receive TDF/FTC and 40% received ABC/3TC by investigator choice.
The results of the study were excellent in both arms with 88% and 85% of participants with HIV RNA levels less than 50 c/mL at 48 weeks slightly favoring the DTG arm and meeting the non-inferiority objective (95% confidence interval: -2.2%, 7.1%) and CD4 rises were virtually identical in the two arms. Both arms showed the very rapid virologic response that we now associate with InSTI-based therapy. Discontinuations due to AE were very uncommon (2% vs. 1%) and overall discontinuation rates for non-virologic reasons were 7% in both arms. A testament, I believe, to the tolerability of each of the two regimens. Virologic nonresponse was slightly lower in the DTG arm (5% vs. 8%), which provides the overall margin of difference at 48 weeks. Response rates were very similar between arms when the results were broken out by NRTI combination and treatment arm. An eye-ball comparison across NRTI backbones based on my calculations of the presented data also showed very similar outcomes (425/489 or 87% for TDF/FTC and 287/333 or 86% for ABC/3TC). Response rates for the sub-groups above and below 100,000 c/mL were not statistically different between arms. In the < 100,000 c/mL group 90% of DTG treated participants and 89% of RAL-treated participants had HIV RNA < 50 c/mL in the 48 week snap shot window. In the > 100,000 group the proportions were lower in both groups and more so with RAL (82% vs. 75%) though the difference was not significant as the number of participants with higher VL was less. I need to point out that the study did have a very strict definition of virologic failure. Participants were considered virologic failures it they had two HIV RNA levels > 50 c/mL at or after 24 weeks and virologic failures were required to go off the study so there was no opportunity to see if patients with low level viremia would re-suppress. I will discuss this more below but it is possible that patients with very high viral loads could have still been on the way down at 24 weeks -for example a viral load of 110 c/mL at week 24 followed by a viral load of 55 c/mL 4 or more weeks later would be a virologic failure. Looking at the typical outcome graph that was presented it does not appear that this scenario occurred commonly but it would be good to know if some of the "failures" were still on the way down when they "failed" and were taken off study. Bottom line though is that the success rates might even have been better if a different definition of virologic failure were used. Protocol defined virologic failure occurred in 20 patients on DTG and 28 patients on RAL. 19 of the 20 PDVF on DTG failure with VL in the 50-400 range and 23 of the 28 PDVF on RAL-based therapy also failed in this range.
Resistance testing was attempted on all virologic failures regardless of VL. Eight of 20 patients with PDVF on DTG-based therapy had successful integrase genotyping and 12 had RT/PRO results. No resistance to DTG or to NRTI was demonstrated. So as yet resistance emergence to DTG has not yet been demonstrated in treatment naïve patients and the lack of NRTI mutations suggests perhaps that DTG may protect against resistance emergence to other medications in the combination. In STARTMRK and the studies of the "Quad" (elvitegravir/cobicistat/TDF/FTC) in naïve patients resistance emergence occurred in a small fraction of randomized subjects but when resistance emerged resistance to both the integrase and NRTI was common[2-4]. The resistance results of Spring 2 need to be carefully considered in the context of the protocol definition of virologic failure. Most patients (in both arms) with PDVF has low VL and were "early" failures. Only 1 of 18 patients with PDVF on RAL-based therapy who had integrase genotyping had known RAL resistance mutations. A substantially lower percentage than in other integrase studies in naïve patients and 3 of 19 patients with RT/pro genotype results had M184I/V. While it is accurate to say there were no resistance mutations detected in patients with PDVF on the DTG arm opinions about the pharmacologic/genetic barrier to resistance of regimens with DTG plus 2 NRTI are just that - opinions.
Adverse event rates in the two treatment arms showed no significant or substantial differences in any category suggesting that DTG plus 2 NRTI is likely to be as well tolerated in clinical practice as RAL-based therapy. Grade 3 and 4 drug-related AE and drug-related serious adverse events were very uncommon in both arms in the blinded study and AE resulting in withdrawal of therapy occurred in only 2% of subjects in each arm. Laboratory abnormalities were also uncommon and similar between arms with no apparent "signal" for DTG. Total cholesterol and TG increased minimally in both arms; unlikely to be of any clinical significance.
Dolutegravir (like cobicistat) does block renal secretion of creatinine in the proximal tubule of the kidney. Though the transporter that is blocked is different than with cobicistat the effect on creatinine is very similar (on the order of 0.14-0.15 mg/dL) and this increase does not represent a decrease in renal function. In Spring 2, no patient discontinued therapy due to a renal event. Obviously DTG is not "linked" to TDF in the same way as cobicistat so there may be more options if a change in estimated creatinine clearance raises uncertainty for a specific patient who may have had a borderline estimated creatinine clearance at baseline when started on DTG plus TDF/FTC compared to a fixed dose combination regimen.
Overall these data are very encouraging for DTG plus 2 NRTI in treatment navie patients and the resistance data are intriguing. We also know from a press release that the second phase III study of DTG in treatment naïve patients that DTG plus ABC/3TC was superior to the fixed dose combination of EFV/TDF/FTC in a blinded study and the proportion of participants on DTG plus ABC.3TC who were suppressed to < 50 c/mL at 48 weeks was 88% (the same percentage reported in Spring 2). Outcome data based on baseline HIV characteristics (VL > 100,000, CD4 < 200) will be very interesting as will the resistance data and hopefully these data will be presented soon.
IAC: Once-Daily Dolutegravir(DTG; S/GSK1349572) is Non-Inferior to Raltegravir (RAL) in Antiretroviral-naïve Adults. 48 Week results from SPRING-2 (ING113086) - (07/26/12)
Cobicistat
The first phase III study of cobicistat as a booster of a protease inhibitor in treatment naïve patients was presented at IAC by Joel Gallant. This is a very straight-forward double-blind, placebo controlled study that compares cobicistat boosting of atazanavir to ritonavir boosting of atazanavir both combined with TDF/FTC. The study was powered for 12% non-inferiority margin, approximately 345 patients were randomized in each arm and 48 week results were presented. eGFR has to be > 70 mL/min to enter the study. Once again study participants were predominantly men (approximately 83%), though the proportion of non-white participants was higher than in other recent phase III studies (~ 40%). The proportion with VL > 100,000 c/mL was also around 40% and the proportion with CD4 < 200 was 16.5%.
The results of this study are equally straightforward. The proportion less than 50 c/mL by the "snapshot" analysis was 85% in the cobicistat arm and 87% in the ritonavir arm, well within the bounds of non-inferiority (95% CI -7.4% to 3.0%). CD4 responses were similar. Virologic nonresponse was low (6% vs. 4% accounting for the overall difference) and 9% in each arm either discontinued study drug due to AE or other reason prior to the week 48 window with an HIV RNA < 50 c/mL or had data missing in the window. Response rates above or equal to or below 100,000 c/mL were very similar between arms as were response rates by CD4 strata (>350 or < 350 cells/mm3). Subjects who experienced either suboptimal virologic response (HIV-1 RNA ≥50 c/mL and <1 log10 below baseline at Week 8 and confirmed at the subsequent visit), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50 or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at Week 48 or their last visit (at or after Week 8) had resistance testing attempted (note the difference in the definition than in the Spring 2 study). Only 12 patients in each arm met one of these criteria. As in virtually every other study of boosted PI therapy in treatment naïve patients no primary PI mutations were observed in either arm. Emergence of NRTI mutations was also uncommon with only 2 participants (both on the cobicistat arm) developing an M184V/I mutation and none developing K65R.
Careful scrutiny of the adverse events and listing of lab abnormalities does not reveal any substantial differences between the two arms. A slightly higher percentage of RTV-treated participants had diarrhea but this was not noted a being a significant difference. Study drug discontinuation due to AE was 7.3% and 7.2% in this blinded study. There was a trend for greater increases in total cholesterol and triglycerides in the RTV-treated arm but the numerical differences were small and unlikely to be important clinically. Six vs. 5 individuals discontinued study treatment due to renal adverse events in the cobicistat vs. RTV arms respectively with 5 vs. 2 having "proximal tubulopathy". When the overall results of a large study look very good we have a tendency to look hard at small differences but it is hard for me to generate much concern over these very small and non-significant differences. As we have seen in other studies there was a greater change in creatinine related to the known greater effect that cobicistat has on creatinine secretion compared to RTV. Median increases were small and predictable (0.13 in the cobicistat arm and 0.09 mg/dL in the RTV arm) at 48 weeks.
So what is the overall clinical message of these results. One could look at the results in two ways. One way would be to say that cobicistat really isn't much different than ritonavir. Sifting through the efficacy, safety and AE results I am hard pressed to find any meaningful clinical differences or even a suggestion of a meaningful difference between these two agents that are apparent from this study. Cobicistat does not induce liver enzymes like RTV so drug-drug interactions may be somewhat less but like RTV it is a potent p450 3A4 inhibitor so most of the drug-drug interactions remain. On the other hand the other way to look at it is that it is very very similar to ritonavir but it is not ritonavir. Co-formationulation work is already underway with atazanavir and darunavir and if things move forward as expected we may eventually have a co-formulated boosted PI that is not lopinavir/ritonavir. In addition, the possibility for a co-formulated single pill boosted PI regimen is made possible by the success of cobicistat - though this development is also predicated on the success of the next generation pro-drug of tenofovir, GS-7340.
IAC: Cobicistat versus Ritonavir as Pharmacoenhancers in Combination with Atazanavir Plus Tenofovir DF/Emtricitabine: Phase 3 Randomized, Double Blind, Active-Controlled Trial, Week 48 Results - (07/24/12)
Elvitegravir/cobicistat/TDF/FTC (QUAD)
Additional data form the two pivitol phase III studies of the "QUAD" in treatment naive were presented as posters at IAC. Both these studies have been published [2],[3] recently. The data at IAC focused on treatment response by baseline HIV RNA levels and CD4 strata. The first, which compared two single tablet regimens (QUAD vs. FDC efavirenz/TDF/FTC) in a randomized double-blind comparison, was presented by Paul Sax. The overall 48 week results of this study demonstrated that FDC ELV/cobi/TDF/FTC was non-inferior to EFV/TDF/FTC with 88% of participants on ELV/cobi/TDF/FTC and 84% of participants on EFV/TDF/FTC having HIV RNA < 50c/mL in the FDA "snapshot" analysis. In this poster results were shown for 3 baseline viral load strata; < 100,000, between 100,000 and 400,000 and > 400,000 c/mL. There were no statistically significant differences between the 2 treatment arms in any of the 3 strata and no real trend in the response across the strata. In the two lower strata the proportion < 50 c/mL at 48 weeks numerically favored ELV/cobi/TDF/FTC and in the > 400,000 c/mL at baseline group the proportion responding to ELV/cobi/TDF/FTC was slightly and not significantly lower than with EFV/TDF/FTC (86% vs. 90%). The numbers in this stratum were small; 50 patients total out of the 700 randomized. No explanation was provided for splitting the analysis into 3 viral load strata and how the higher cut point was made. Responses by baseline CD4 cell count (< 200, 201-350 and > 350 cells/mm3) were also shown and again there was no significant difference between arms in the 3 CD4 sub-categories. Like many other EFV-based studies in treatment naïve patients presented in the past there seemed to be almost no impact of baseline CD4 on response to ELV/cobi/TDF/FTC with response rate of 82%, 84% and 84% in the three rising strata. Response rates were a little more variable in the EFV/FTC/TDF arm with 74%, 87% and 91% in the rising strata and certainly similar to what we have seen with other combination regimens. There were only 43 participants in the < 200 cells/mm3 sub-group and very few (as I understand it) with baseline CD4 cell counts < 50 cells/mm. Response by adherence sub-group (< 95% or > 95% was also presented and again there were no significant difference between treatment arms in any strata. Overall those participants who endorsed outstanding adherence (>95%) did numerically better than those with < 95% adherence in both treatment arms.
The sister study, presented by Edwin DeJesus (and recently published [3]), compared ELV/cobi/TDF/FTC with atazanavir, ritonavir and TDF/FTC in a very similar randomized, double-blind design. This study also showed non-inferiority at the 48 week primary endpoint with 90% vs. 87% of participants having HIV RNA < 50 c/mL in the FDA snapshot analysis for ELV/cobi/TDF/FTC and ATV/r plus TDF/FTC respectively. Like the study by Sax et al these patients were mostly men (~90%), mostly white (75%) and few had advanced HIV disease (< 15% with CD4 < 200 cell/mm3 at baseline). Long story short - there were no significant differences between treatment arms in the 3 viral load strata (< 100,000, 100 - 400,000 and > 400,000) or by CD4 cell count. The poster did not appear to have any new safety or resistance data. Resistance emerged in 1% of subjects on the ELV/cobi/TDF/FTC arm (compared to 2% in the study by Sax et al) and almost all of the participants in both studies who developed resistance developed both InSTI and NRTI resistance. In this study, recall that only individuals with viral loads > 400 c/mL were evaluated for resistance. Discontinuations due to renal events were uncommon in this study (one in each arm).
The FDA approval of the fixed dose combination of ELV/cobi/TDF/FTC (QUAD) is expected any day now.
IAC: Analysis of Efficacy by Baseline HIV RNA - Week 48 Results from a Phase 3 Study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Quad) Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects - (07/26/12)
IAC: Analysis of Efficacy by Baseline Viral Load: Phase 3 Study Comparing Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Quad) versus Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects: Week 48 Results - (07/25/12)
Treatment naïve patients with advanced disease
Unfortunately all of us still see very advanced patients present for HIV care, sometimes just with very low CD4 cell counts but also with opportunistic infections or cancer. Perhaps the number of patient who present this way is declining. One thing is for sure - these patients rarely make it into our clinical trials evaluating new agents for treatment naïve patients. Therefore our experience with the "QUAD", dolutegravir-based therapy and cobicistat boosting of PI in treatment naïve patients who present with very advanced HIV-disease will need to come from clinical practice or phase IV clinical trials. I don't see any evidence from the trials presented so far that raises a concern for any of these new agents but we have to be aware that the clinical trial data are limited. The large HIV cohorts in the US and Europe perhaps have a responsibility to track and assemble these data over time to confirm our sense that these new agents will be similarly effective across all patients presenting for initiation of HIV therapy.
Agents in Earlier Clinical Studies
S/GSK1265744
S/GSK1265744 (744) is a very interesting integrase strand transfer inhibitor being developed by Shionogi, ViiV and GSK. 744 is a sister compound to dolutegravir and has similar very potent antiretroviral activity when given as an single drug oral agent over a 10 day course at low mg doses (5 or 30 mg orally) producing 2.5 log10 declines in plasma HIV RNA over this short period. The in vitro resistance profile is "favorable" and all together this would make 744 a very solid back up to dolutegravir. However, 744 has some other interesting properties. 744 has a relatively long-half life when given orally. This InSTI has low aqueous solubility and correct particle size to control release kinetics and can be formulated as a nano-suspension that is stable with a relatively low volume. All of these factors put together makes for an agent that can be considered for delivery as an injectable antiretroviral which could be delivered as infrequently as once per month or perhaps longer.
Bill Spreen presented a poster on 744 that provided the first look at the safety and pharmacokinetic of single intramuscular (IM) or subcutaneous (SC) doses of S/GSK1265744 long-acting nano-suspension in healthy HIV-uninfected adults. Single dose of 100 to 800 mg were tested with the 400 mg SC and the 800 mg IM injections requiring two shots. There were 8 subjects in each of seven groups (6 active drug and 2 placebo for blinded assessment of safety). These single shots were fairly well tolerated. Injection reactions may have been more common with the SC injections but the reactions were generally reported as mild. There were no serious adverse events or lab abnormalities reported. The estimated half-life ranged from 20 -50 days depending on dose and at the higher doses the concentration remained well above the protein corrected IC90 for wild-type virus for 8-12 weeks. Some subjects still have measureable concentrations a year after a single dose.
Research scientists, clinicians, advocates and patients have argued about the value of an injectable agent for the treatment and/or prevention of HIV infection. There is no consensus on how valuable such agents would be but there is some agreement on several issues 1) for treatment, mixing oral and injectable drugs is unlikely to be very successful and two or more injectable agents with similar half-lives will be needed, 2) a successful injectable combination therapy will benefit some HIV-infected individuals (the argument is really about is this a lot or a little or in between) and 3) a well tolerated safe injectable antiretroviral agent with a long half-life would likely address some of the adherence issues that face pre-exposure prophylaxis (PrEP) interventions. In this context the 744 data are interesting and perhaps 744 could be used as a single agent for PrEP (especially if it has a high barrier to resistance), but what about a partner for the treatment of HIV infected persons. Many of the readers of this article probably know that rilpivirine is also being investigated as a long-acting nano-suspension[5]. Perhaps these two compounds could be used together? According to clinicaltrials.gov a study beginning to investigate the PI of these two compounds given to healthy HIV-uninfected volunteers in now recruiting
(http://www.clinicaltrials.gov/ct2/show/NCT01593046?term=rilpivirine&rank=2).
In addition, a study has just started to help define the activity of these to medications given together as oral agents. The study, called LATTE, enrolls treatment naïve patients and randomizes them to receive one of 3 oral doses of 744 plus NRTI of choice (TDF/FTC or ABC/3TC) or EFV plus choice of the same NRTI (http://www.clinicaltrials.gov/ct2/show/NCT01641809?term=rilpivirine&rank=18). If participants on the 744 arms suppress their viral load then at week 24 their NRTI will be switched to oral rilpivirine and they will be followed for an additional 72 weeks (as will the comparator arm). Why is this study important? One obvious reason is to assess the tolerability of these two medications given together for a long period. The second reason is to see whether these two agents can sustain virologic suppression for a prolonged period in a population for whom it is probably relatively safe from a virologic point of view. There have been few dual therapies that have been safe and effective and no combination of an InSTI plus an NNRTI tested in HIV-infected individuals (that I know of). Testing these to drugs together as oral agents also makes sense as even if the dual injection therapy proves to have adequate PK and anticipated good antiretroviral activity one could imagine that the medications would be given orally for a period of time to each individual patient to make sure there is no unexpected toxicity or allergy given that 744 LAP and rilpivirine LA can be measure in blood plasma months after a single injection.
IAC: Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults - (07/25/12)
Additional new agents in early development
BMS-986001 (festinavir)
BMS-986001 is a NRTI that is in phase IIb clinical trial in HIV-infected treatment naïve individuals in combination with 3TC and efavirenz. This compound has some structural similarities to d4T (stavudine) and therefore it deserves a clear evaluation for metabolic toxicity. These authors showed that in vitro 986001 did not reduce cellular mitochondrial DNA in several different human cell types and had no cytotoxicity at the doses tested. These results compared favorably to d4T and were similar or slightly better than with tenofovir or abacavir. These in vitro results are encouraging though one could ask whether we really need another first-line NRTI? Tenofovir DF and abacavir certainly have limitations and long-term effects on renal function, bone and cardiovascular risk may be the biggest concerns. The conundrum of course is how does one develop a new agent to avoid very long-term side effects (measure in years or even decades) that may or may not be predictable? In vitro studies are a good start but it is an uphill climb.
IAC: THE HIV NRTI BMS-986001 DOES NOT DEGRADE MITOCHONDRIAL DNA IN LONG TERM PRIMARY CULTURES OF CELLS ISOLATED FROM HUMAN KIDNEY, MUSCLE AND SUBCUTANEOUS FAT - (07/25/12)
IAC: Absence of renal and bone toxicity in non-clinical studies of BMS-986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV) - (07/25/12)
BMS-663068
BMS-663068 is a prodrug for BMS-626529, which is an attachment inhibitor (AI) that blocks the HIV env:CD4 interaction by binding to HIV envelope gp120. The BMS -663068 is in phase IIb clinical development. This drug, which is directed at a novel target (binding to the virus envelope) may be very useful for those patients I mentioned at the very start of the article who have 3 and 4 drug class resistance. As mono-therapy, this drug resulted in a 1.64 log10 decline in HIV RNA over an 8-day period. However some viruses are intrinsically resistant to the AI and in the proof of principal study approximately 10% of patients had a < 1.0 log10 decline in plasma HIV RNA over the 8-day period. In a poster at IAC investigators at BMS presented data on mechanism of resistance to 626529 and on cross-resistance between entry inhibitors. One concern raised about AI was that resistance might be due to viruses becoming CD4 independent (i.e. bypassing CD4). To date, while CD4 independent viruses can be created in the lab they have never been demonstrated in HIV-1 infected individuals. The in vitro studies presented in this poster demonstrated that lab-created, CD4 independent, HIV-1 were still susceptible to BMS-626529 and that the viruses with decreased susceptibility to the drug were NOT CD4 independent. Also these in vitro studies showed that enfuvirtide (T-20) resistant variants and ibalizumab resistant variants were susceptible to the attachment inhibitor. Some MVC resistant variants were also resistant to the AI though the mechanisms of resistance did not seem to be linked. Finally viruses with decreased susceptibility to the AI retained susceptibility to all other entry inhibitors.
IAC: Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors - (07/25/12)
Still in the Game
While there were no data presented at IAC Merck has a 'second generation' NNRTI (MK-1439) that is starting phase IIb development. A press release announced that a study of this once daily medication in treatment naïve patients is likely to begin in September
(http://www.clinicaltrials.gov/ct2/show/NCT01632345?term=MK-1439&rank=1)
Merck Signs Two Deals for Novel HIV Drug Candidates and Initiates Phase II Clinical Trial of MK-1439 for HIV - (07/25/12)
.....CMX157, new nucleoside reverse transcriptase inhibitor; EFdA, new nucleoside reverse transcriptase inhibitor
Collaborators with Pfizer presented very early in vitro data on a series of compound called LEDGINs. These compounds were developed to block an important interaction between the HIV integrase and a human (host) protein LEDGF/p75. Perhaps, as a bit of a surprise, these compound also demonstrated an ability to block HIV-1 integrase catalytic activities via a mechanism that appeared to be different than the current strand transfer inhibitors like raltegravir and elvitegravir. These investigators showed inhibition of HIV-1 replication in in vitro in two cell types including human PBMC cells and they appeared to be active across HIV-1 sub-types. Importantly LEDGINs were active against a panel of viruses containing mutations that confer resistance to raltegravir and elvitegravir and there appeared to be in vitro synergy between LEDGINs and the standard integrase inhibitors. In addition the lead LEDGIN compound appears to also decrease the infectivity of virus released from infected cells though the mechanism for this decrease in infectivity is not fully understood. Clearly these are very EARLY days but these compounds did look quite potent and while these LEDGINS are not directed against a novel target they seem to inhibit HIV-1 integrase by a new mechanism. We will have to pay attention and look for additional data on these compounds.
Abstract
Powerpoint
Webcast
http://pag.aids2012.org/flash.aspx?pid=1270
Abstracts
Francois Raffi, Anita Rachlis, Hans-Jurgen Stellbrink, David Hardy, Carlo Torti, Chloe Orkin, Mark Bloch, Daniel Podzamczer, Vadim Pokrovsky, Steve Almond, David Margolis, and Sherene Min on behalf of the extended SPRING-2 study team. Once-daily Dolutegravir (DTG; S/GSK1349572) is Non-inferior to Raltegravir (RAL) in Antiretroviral-naive Adults. 48 Week Results from SPRING-2 (ING113086) THLB
Joel Gallant, Ellen Koenig, Jaime Andrade-Villanueva, Ploenchan Chetchotisakd, Edwin DeJesus, Francisco Antunes, Keikawus Arasteh, Graeme Moyle, Giuliano Rizzardini, Jan Fehr, YaPei Liu, Lijie Zhong, Christian Callebaut, Srini Ramanathan, Javier Szwarcberg, Martin Rhee, Andrew Cheng. Cobicistat versus Ritonavir as Pharmacoenhancers in Combination with Atazanavir Plus Tenofovir DF/Emtricitabine: Phase 3 Randomized, Double Blind, Active-Controlled Trial, Week 48 Results
P Sax, E DeJesus, A Mills, A Zolopa, C Cohen, D Wohl, JE Gallant, HC Liu, L Zhong, K Yale, K White, B Kearney, J Szwarcberg, E Quirk and A Cheng. Analysis of Efficacy by Baseline HIV RNA - Week 48 Results from a Phase 3 Study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Quad) Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects
E DeJesus, JK Rockstroh, K Henry, J-M Molina, J Gathe, S Ramanathan, X Wei, J Szwarcberg, M Rhee, A Cheng. Analysis of Efficacy by Baseline Viral Load: Phase 3 Study Comparing Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Quad) versus Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects: Week 48 Results
W Spreen, SL Ford, S Chen, E Gould, D Wilfret, D Subich, T Taishi, Z Hong. Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults. Abstract TUPE040
F Wang and O Flint. The HIV NRTI BMS-986001 Does not degrade mitochondrial DNA in long term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat.
Zhufang Li, Nannan Zhou, Yongnian Sun, Neelanjana Ray, Max Lataillade, George J Hanna, Mark Krystal. Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors.
F. Christ, C. Pickford, J. Demeulemeester, S. Shaw, B.A. Desimmie, C. Smith-Burchnell, S. Butler, M. Westby, Z. Debyser. Pre-clinical evaluation of HIV replication inhibitors that target the HIV-integrase-LEDGF/p75 interaction TUAA0301
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