The Body Covers: The 11th Conference on Retroviruses and Opportunistic Infections
New Antiretroviral Drugs in Development
February 11, 2004
The need for potent new antiretrovirals is obvious to anyone who treats people living with HIV infection. Drug resistance and intolerance limit the benefits of the current slate of HIV medications. As the long-term consequences of HIV therapy manifest themselves in vanishing facial fat and elongating lines of resistance-red ink on genotype reports, clinicians are hard-pressed to craft yet another salvage regimen with whatever leftover antiretrovirals remain.
Fortunately, therapies that are less toxic, more convenient and active against drug-resistant virus are in the early stages of development in each of the major drug treatment classes: entry inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Results from several of these efforts were reported at the 11th CROI.
NRTIs are considered the backbone of combination HIV therapies. However, extensive use of these agents has led to increased rates of NRTI resistance among not only treatment-experienced patients but also patients who are naive to treatment. Recent data from the United States and Europe indicate that drug-resistant HIV can be acquired through sexually transmitted HIV, with NRTI resistance the most prevalent. In the Catch Study presented at the International AIDS Society meeting last year, researchers examined the frequency of genotypic resistance among 1,400 individuals with recently acquired HIV infection in 16 European countries between 1996 and 2002.1 Almost 10% of these drug-naive patients were found to have evidence of antiretroviral resistance, 7% with NRTI-resistance mutations.
Similarly, at CROI, evidence that preexistent drug resistance can influence clinical response to therapy was provided by a study that compared emtricitabine (FTC, Emtriva)/didanosine (ddI, Videx) versus stavudine (d4T, Zerit)/didanosine, when combined with efavirenz (EFV, Sustiva, Stocrin) in treatment-naive subjects.2 At baseline, 42 of the 571 participants were found to have evidence of NRTI resistance, which is similar to the rate observed in the Catch Study. NRTI resistance at study entry was predictive of virologic failure among those on the stavudine arm.
As the prevalence of transmitted drug resistance increases and, as on-treatment failures continue to occur during treatment with NRTI-containing regimens, the need for agents that are active against NRTI-resistant mutants increases. If such an agent was also free of the mitochondrial toxicity associated with most members of this antiretroviral class, this would be a major advance in HIV care. At CROI, studies of two promising new cytidine analogues, SPD-754 and Reverset, were presented. They offer a hopeful glimpse at what the NRTI of the future will look like.
SPD-754 is the (-) enantiomer of a previously studied compound, dOTC, which had unacceptable rates of toxicity, halting its further study. SPD-754 appears to be much better tolerated and in vitro data suggest the drug is active against NRTI-resistant HIV-1, including virus resistant to another cytidine analogue, lamivudine (3TC, Epivir).
A dose-ranging study3 of SPD-754 was conducted in 63 HIV-infected, treatment-naive (<7 days) individuals (43% of whom were women) randomized to one of six doses of SPD-754 or placebo. The study found a respectable reduction in HIV viremia following 10 days of monotherapy. The median baseline plasma HIV RNA level was 4.3 log10 copies/mL and the median CD4+ cell count was 450 cells/uL. The lowest dose of SPD-754, 400 mg, produced a 1.18 log10 decline in viral load. The 1,200-mg and 1,600-mg arms experienced a greater than 1.5 log10 reduction.
SPD-754 had significant antiviral activity even among the four participants who had baseline NRTI resistance. On therapy, no new NRTI mutations emerged in these patients.
Safety data from this trial, which was conducted in South Africa, Thailand and Argentina, were not presented. An accompanying oral presentation of the in vitro and in vivo investigations of the co-administration of SPD-754 and lamivudine demonstrated no pharmacokinetic interaction between these analogues. However, lamivudine markedly reduced the intracellular concentration of phosphorylated SPD-754, indicating co-administration will likely not be feasible.4
Another cytidine analogue, Reverset or D-D4FC, was studied in a similar small pilot study of 30 HIV-infected subjects. Prior studies of Reverset have demonstrated activity against wild-type HIV-1 and HIV-2 as well as virus resistant to lamivudine, zidovudine (ZDV, Retrovir) and other NRTIs.
However, in vitro, the multi-drug resistant Q151M mutation and the 69 insertion produce highly reduced susceptibility to Reverset, while the K65R mutation leads to a three-fold reduction in susceptibility. Reverset's long intracellular half-life (more than 17 hours) bodes well for once-daily administration.
In this 10-day, dose-escalation trial, subjects with a viral load of more than 5,000 copies/mL and a CD4+ cell count of more than 50 cells/uL were randomized to 50 mg, 100 mg or 200 mg of active drug or placebo once daily. At baseline, the median plasma HIV RNA levels among the arms were between 4.24 and 4.81 log10 copies/mL. The median CD4+ cell counts were between 353 and 645 cells/uL. All viral genotypes had wild-type patterns at entry.
After 10 days, viral load declined by 1.67, 1.74 and 1.77 log10 copies/mL in the 50-mg, 100-mg and 200-mg arms, respectively. CD4+ cell counts climbed in the active-treatment arms. There were no significant clinical or laboratory adverse events reported.
SPD-754 and Reverset may be a boon to future salvage therapy. Importantly, neither agent has in vitro evidence of mitochondrial toxicity. In addition, with the current heavy reliance on zidovudine + lamivudine + efavirenz as initial therapy, subsequent salvage regimens must often contend with a lamivudine-associated M184V mutation, the NNRTI class killing mutations (e.g., K103N) and sometimes thymidine analogue mutations.
Salvage therapy needs NRTIs that can be used against NRTI-resistant virus. Both of these new agents seem to fit this role and may be ideal second-line agents. Their adoption as first-line antiretrovirals hinges on their comparative potencies, resistance patterns, long-term tolerabilities and cost.
As an intracellular interaction between lamivudine and SPD-754 has been demonstrated, extensive future study of antagonism between lamivudine and, by extension, emtricitabine and Reverset and between Reverset and SPD-754 will also be required.
Arguably, there is no antiretroviral class more in need of a new and improved addition than the NNRTIs. Like Achilles, the mightiest of Greek warriors, this is a mighty antiretroviral class that reins in huge market share as a component of first-line therapy. However, unlike Homer's hero, it is not just a spot on the heel that marks the weakness of these agents, but a huge vulnerability to resistance that, once it develops, cripples the class and complicates salvage regimens. Additionally, as in the case of transmitted NRTI resistance, acquisition of virus that is NNRTI resistant can hamstring HIV management. At present, there is a low rate of transmitted NNRTI resistance. In fact, in the Catch Study,1 less than 3% of the patients had NNRTI resistance mutations. However, as expected, with increased reliance on this antiretroviral class, NNRTI resistance is increasing. For example, in a study of newly HIV-infected individuals conducted in San Francisco, NNRTI-associated mutations increased from 0% during 1996-1997 to 13.2% in the period from 2000-2001.5 Therefore, it is understandable that a Holy Grail of drug development has been the creation of an NNRTI with activity against K103N mutant virus.
TMC-125 is the leading contender to be the first next generation NNRTI. Previous studies have demonstrated that this compound is active against NNRTI-resistant strains of HIV-1. It has a novel structure that is relatively flexible, allowing for adjustment in shape to mutational changes in its target and avid binding to the site. Initial clinical investigation demonstrates its overall potency; however, this may be attenuated in patients with significant NNRTI resistance.6
There was not much new data about TMC-125 presented in San Francisco. A poster7 detailing an in vitro investigation of the activity of TMC-125 against increasingly NNRTI-resistant virus was presented.
By first examining the phenotypic susceptibility of TMC-125 among over 5,600 clinical isolates, the investigators identified mutations associated with resistance to the drug and, along with other resistance data, constructed isolates containing single, double and triple TMC-125 mutations.
The panel of single mutants contained known NNRTI mutations, such as K103N, as well as mutations that have been selected for in vitro by TMC-125 and mutations identified among clinical isolates (i.e., K101P and Y181I).
Of the 59 single mutants created and tested, four demonstrated a greater than 10-fold reduction in susceptibility to TMC-125: Y181I, Y181V, F227C and M230L. These mutations were observed to be relatively rare (<2%) in a database of over 7,000 isolates known to be resistant to NNRTIs.
Accumulated resistance, as expected, led to reduced antiretroviral activity. Double mutant constructs containing V179F and Y181C conferred over 100-fold resistance to TMC-125. Again, this mutational duo is rare (<1%) among isolates resistant to the current crop of NNRTIs, although Y181C itself is common -- observed in 37% of the NNRTI-resistant clinical isolates. A number of triple-mutant strains containing at least K103N and L100I were also evaluated and several conferred high-level resistance to TMC-125.
These data demonstrate that this new NNRTI may be bulletproof, but it is hardly bomb proof against some of the resistance mutations that are seen in NNRTI-experienced patients, particularly when select mutations are present in combination. Fortunately, these mutations are relatively rare at this point. Phase II trials of TMC-125 are underway.
Preclinical data8-10 from a number of different pharmaceutical companies indicate that the hunt for a better NNRTI continues. Whether any of these will advance to clinical testing, as TMC-125 has, remains to be seen.
Certainly, as mentioned previously, the potency of NNRTIs is clear. These are the most popular drugs used in first-line therapies today. Their weak spot, of course, is their low genetic barrier to resistance. The significance of agents that are active against NNRTI-resistant virus, less susceptible to rapid resistance and well tolerated should not be underestimated. Such drugs may herald a new era in HIV therapy. Can there be any finer lure to entice pharma?
The supremacy of PIs as the anchor in initial combination HIV therapy has faded in the face of the well-demonstrated potency of NNRTIs, adverse effects associated with the PI class and the popularity of triple-nucleoside therapy. However, PIs have made a resurgence. Last year, lopinavir/ritonavir (LPV/r, Kaletra) earned a coveted spot on the U.S. Department of Health and Human Services' short list of recommended first-line therapies.11 In addition, over the past few months, atazanavir (ATV, Reyataz) has become the hit antiretroviral sensation of the year.
As is the case for the other classes of HIV therapy, though, there is a need for PIs that are more convenient, less toxic and active against resistant virus. Data on what will likely be the next addition to the PI class, tipranavir, was absent at CROI while this drug enters the homestretch toward approval.
At last year's CROI, data presented from a dose-ranging study provided evidence of the potency of tipranavir when combined with ritonavir (RTV, Norvir) in treatment-experienced patients.12,13 In that study, 0.9 to 1.2 log10 decreases in viral load were observed across three treatment doses of tipranavir/ritonavir twice a day (500/100, 500/200, 750/200). Based on combined antiviral effect and tolerability, the 500/200 dose was chosen for further large-scale clinical evaluation; however, given the recent increase in the price of ritonavir, there remains some interest in exploring the 500/100 dose. The next we hear about this twice-a-day PI will likely be in the form of a press release once it's been approved.
After the approval of tipranavir, it remains unclear what the next new PI will be. Early results suggest that TMC-114 is a leading contender.
Another drug being developed by the maker of TMC-125 is TMC-114. This PI has been studied in HIV-infected persons during a two-week, dose-ranging trial in which patients failing PI-based therapy either substituted their current PI for TMC-114 along with 100 mg of ritonavir or continued their PI.14 An average decline in viral load of 1.35 log10 was observed in the TMC-114/ritonavir arm, demonstrating the efficacy of this boosted PI.
A follow-up study,15 presented at CROI, examined the influence of baseline genotypic and phenotypic PI resistance and response to TMC-114/ritonavir among 38 subjects randomized to receive the compound. Whether a subject had a single-PI mutation, phenotypic resistance to all current PIs except atazanavir (which had not been approved at the time this study was performed), or high-grade lopinavir (LPV) resistance by phenotype at baseline, the median change in viral load at day 14 was -1.4 to -1.5 log10 copies/mL.
In another study, much like the one presented on TMC-125, the activity of TMC-114 against a host of resistant viral isolates was reported.16 A data set of 5,601 isolates, of which 2,202 were known to be PI resistant (greater than four-fold decreased susceptibility), was tested and TMC-114 appeared to be active against strains resistant to anywhere from one to seven PIs and those containing one to three primary PI-resistance mutations. Activity here was defined as having a less than four-fold decrease in susceptibility.
Overall, TMC-114 appears promising. However, its current liquid formulation, which contains polyethylene glycol (PEG, CoLyte, GoLYTELY) to increase bioavailability, may be associated with a high rate of gastrointestinal adverse effects. Data on lipids and glucose will need to be evaluated during long-term studies. In addition, how this boosted PI will stack up clinically against lopinavir/ritonavir -- a drug whose activity is measured in terms of having a less than 10-fold reduction in susceptibility -- remains to be seen.
The most exciting compounds in development are those that inhibit HIV's entry into the cell. In a surprisingly short period of time, clinicians have become more comfortable with entry inhibitors -- once considered a Star Wars-like approach to HIV therapy. Demand for enfuvirtide (T-20, Fuzeon) is increasing and the demise of T-1249, a next-generation entry inhibitor, ascribed by its manufacturer to production difficulties, generated an outcry in the HIV community. However, clinicians and patients are looking beyond enfuvirtide to newer compounds that are easier to administer (read: orally available) and accessible (read: affordable).
Entry inhibitors can be categorized according to the specific point in the process of HIV entry where the agent interferes: i.e., attachment inhibitors, chemokine receptor antagonists and fusion inhibitors. Interesting data on new attachment inhibitors and antagonists of the chemokine receptor were presented at CROI.
BMS-488043 is an oral attachment inhibitor that prevents the binding of the viral envelope protein gp120 to cellular CD4+ receptors, an initial step in the chain of events leading to viral fusion and entry.
The safety and antiretroviral activity of the compound was studied at two twice-daily doses (BID), 800 mg and 1,800 mg, in HIV-infected men and women who were either treatment naive or off of HIV therapy for at least four months and had a CD4+ cell count of at least 250 cells/uL and a plasma viral load of 5,000-500,000 copies/mL.17 (In the interest of full disclosure, this author was a participating investigator in this study.)
Two groups of 15 subjects (12 active/three placebo per group) received 800-mg or 1,800-mg doses of BMS-488043 or placebo exactly every 12 hours for eight days with a high-fat meal. At baseline, the median viral load was 4.77 and 4.65 log10 copies/mL in the 800-mg BID and the 1,800-mg BID cohorts, respectively. The median baseline CD4+ cell count was 413 cells/uL and 372 cells/uL, respectively.
After eight days of therapy, viral load dropped by a median of 0.72 log10 copies/mL in the 800-mg BID arm and 0.96 log10 copies/mL in the 1,800-mg BID arm. There was no change in viral load among patients who received placebo. The agent was well tolerated with no treatment-limiting toxicity observed. Despite the respectable median virologic responses, the range in the degree of viral decay during the short study was relatively wide. This finding may spell the end of the road in the development for this particular compound, one of several in this class under consideration.
There was new data on another attachment inhibitor, TNX-355, a humanized anti-CD4 antibody, engineered by grafting murine proteins onto a human IgG4 antibody construct and then mutating amino acids in the framework to produce a structure that is 95% human. This compound received attention at last year's CROI18 and updated clinical data from HIV-infected patients receiving the compound were presented during a poster19 session at this year's CROI.
In this study, three doses of TNX-355 were administered for nine weeks to 22 subjects who were either off antiretroviral therapy or failing their regimen. In various doses and frequencies, TNX-355 produced about a 1 log10 drop in viral load. However, by week nine, plasma HIV RNA levels returned to baseline and resistance to the compound was detected. CD4+ cell counts, as has been seen in results from earlier studies on this agent, rose and tended to remain elevated. No drug-related serious adverse events were seen.
This is a very novel agent that, if found to be effective and well tolerated in larger trials, may usher in a new approach for the engineering of HIV therapeutics. Using antibodies to interrupt the HIV lifecycle was one of the first strategies to be considered early in the epidemic. However, prior attempts at virus-directed antibody therapy were failures. This agent has proven its ability to reduce HIV viremia, and that is a significant first step. TNX-355 is sure to be subjected to more investigation.
Along with the CD4 receptor, HIV uses the CCR5 receptor to gain entry into the host cell. Blocking of this so-called co-receptor interferes with virus-cell interface and aborts cellular infection. SCH-D is an oral CCR5 receptor antagonist that was studied in 48 HIV-infected individuals who had not received antiretroviral therapy within two months of study entry and had a CD4+ cell count of at least 200 cells/uL.20
Subjects entered three different dosing cohorts:
The subjects were randomized 3:1 to drug or placebo for 14 days. A dose-related increase in antiretroviral activity was seen with mean log10 reductions in viral load of -1.08, -1.56 and -1.62 in the 10-mg, 25-mg and 50-mg BID arms, respectively.
CCR5 antagonists may select for CXCR4 virus, which has been associated with a more rapid decline in CD4+ cell counts and progression to AIDS. Indeed, in this study, a subject with a mixed viral population had his predominantly CCR5 virus replaced by CXCR4 variants, although he did enjoy a 0.5-log10 decrease in his viral load. (This is in contrast to a subject -- in the study of a different CCR5 receptor antagonist, UK-427,857 -- who had a mixed CCR5 and CXCR4 population while on treatment, but whose viral load did not drop and had a reversible predominance of CXCR4 virus.21)
Another individual who was receiving SCH-D had CXCR4 virus detected transiently during the study. SCH-D was reportedly well tolerated, though it should be recalled that SCH-C, a previously studied compound, had worrisome cardiac toxicity. To date, however, this has not been observed with SCH-D. This study also elucidated the metabolic pathway for SCH-D and it appears that there is potential for drug-drug interactions, since this drug is metabolized via pathways other HIV medications also use.
GW-873140 is another CCR5 receptor antagonist that is orally bioavailable and potent in vitro. It was administered to 70 healthy, HIV-uninfected volunteers (57 males, 13 females) at a variety of doses in a double-blind, randomized, placebo-controlled study.22 No serious adverse events and no cardiac-related abnormalities were seen. Co-administration with food increased drug exposure. There is potential for this agent to be administered once a day.
As is obvious, all of these new compounds are in their developmental infancy. It will take years for even the most promising of these drugs to be considered for FDA approval. However, it is a good sign that there are a continuing number of HIV drugs in the early stages of development, particularly in novel areas, such as entry inhibition, which are needed the most by patients who are running out of options.
Lastly, although not the topic of discussion at CROI and unlikely to be mentioned in most reports of "new antiretrovirals," several agents are due to have their patents expire. In 2005, the patent for zidovudine will come to an end, as will the patent for didanosine in 2006. Prior to 2012, patents will also expire for stavudine, lamivudine, abacavir (ABC, Ziagen), saquinavir (SQV, Invirase, Fortovase) and nevirapine (NVP, Viramune). As important as the development of novel new agents is, the availability of generic versions of older HIV drugs can have a significant impact on HIV treatment. The availability of low-priced antiretrovirals will be a boon to the many people both here in the United States and abroad who do not qualify for drug assistance programs but cannot afford their HIV therapies. In addition, with more than 1,200 patients currently waiting for HIV medications on various state-run assistance programs, the expiration of these patents can only be helpful to the states that have been struggling to fund these programs. Clearly, news of the promising results from a study of the next entry inhibitor provide little comfort to those whose 20% co-pay for their medications has led to a second mortgage and/or a second job.
While the pipeline may at times sputter, it is encouraging that many candidate compounds are being investigated. Some of these agents we may never hear of again. Others will enter large-scale clinical study. A couple of drugs may make it to the point where they even get names instead of numbers.
At CROI 2004 we saw potential. However, we also saw that for that potential to be realized, it will take even more time. For now, we wait. In the meantime, we can look forward to the release of a new PI and generic formulations of older HIV medications.
David Wohl, M.D., is an assistant professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections.
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