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Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine.
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PMID:Gateways to clinical trials. 1608 22

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.
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PMID:Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. 1625 17

Maraviroc is a CCR5 antagonist in clinical development as one of a new class of antiretrovirals targeting human immunodeficiency virus type 1 (HIV-1) coreceptor binding. We investigated the mechanism of HIV resistance to maraviroc by using in vitro sequential passage and site-directed mutagenesis. Serial passage through increasing maraviroc concentrations failed to select maraviroc-resistant variants from some laboratory-adapted and clinical isolates of HIV-1. However, high-level resistance to maraviroc was selected from three of six primary isolates passaged in peripheral blood lymphocytes (PBL). The SF162 strain acquired resistance to maraviroc in both treated and control cultures; all resistant variants were able to use CXCR4 as a coreceptor. In contrast, maraviroc-resistant virus derived from isolates CC1/85 and RU570 remained CCR5 tropic, as evidenced by susceptibility to the CCR5 antagonist SCH-C, resistance to the CXCR4 antagonist AMD3100, and an inability to replicate in CCR5 Delta32/Delta32 PBL. Strain-specific mutations were identified in the V3 loop of maraviroc-resistant CC1/85 and RU570. The envelope-encoding region of maraviroc-resistant CC1/85 was inserted into an NL4-3 background. This recombinant virus was completely resistant to maraviroc but retained susceptibility to aplaviroc. Reverse mutation of gp120 residues 316 and 323 in the V3 loop (numbering from HXB2) to their original sequence restored wild-type susceptibility to maraviroc, while reversion of either mutation resulted in a partially sensitive virus with reduced maximal inhibition (plateau). The plateaus are consistent with the virus having acquired the ability to utilize maraviroc-bound receptor for entry. This hypothesis was further corroborated by the observation that a high concentration of maraviroc blocks the activity of aplaviroc against maraviroc-resistant virus.
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PMID:Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. 1718 81

Maraviroc is a specific, slowly reversible, noncompetitive, small-molecule antagonist of the CCR5 chemokine receptor, which also serves as an HIV-1 coreceptor. By acting as an antagonist at the CCR5 coreceptor, maraviroc inhibits HIV-1 from entering host cells. Clinical data for maraviroc are available from two large, well designed, ongoing phase IIb/III trials (MOTIVATE-1 and MOTIVATE-2) conducted in patients infected with R5-tropic HIV-1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and/or were triple-class resistant. According to 24-week interim results of the MOTIVATE-1 and -2 trials, a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg (depending on optimised background therapy [OBT]) twice daily plus OBT compared with placebo plus OBT. This significant difference was maintained at 48 weeks in MOTIVATE-1. In the MOTIVATE-1 and -2 trials, a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV-1 RNA level <400 and <50 copies/mL compared with those receiving placebo plus OBT. In addition, the CD4+ cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT. The 48-week results of MOTIVATE-1 also report a significant difference in favour of maraviroc for all these endpoints. In general, maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment-experienced patients infected with R5-tropic HIV-1.
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PMID:Maraviroc. 1792 88

CCR5 antagonists are a newly developed class of antiretroviral drugs which inhibit viral entry into the host cell by binding to the predominant HIV coreceptor. Data on the use of these new drugs in treatment-experienced HIV patients are emerging. Clinical trials on maraviroc and vicriviroc in pretreated patients recruited more than 1300 individuals. Interim results of these studies indicate that pretreated patients infected with CCR5-tropic viruses benefit from their use in optimized combination regimens. Maraviroc reduces the HIV-1 viral load in patients with previous triple-class failure by 1.96 log10 copies/ml versus 0.99 log10 copies/ml in placebo; vicriviroc shows potency by dose depending viral decrease of 1.51-1.68 log10 copies/ml compared to 0.29 log10 in placebo. As expected, CCR5 antagonists do not reduce viral load in patients harbouring CXCR4-tropic or dual/mixed tropic viruses. Nevertheless, since a considerable percentage of late-stage HIV patients still bear CCR5-tropic viruses, the use of CCR5 antagonists appears promising in properly selected treatment-experienced patients.
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PMID:CCR5 antagonists in the treatment of treatment-experienced patients infected with CCR5 tropic HIV-1. 1793 23

A new class of antiretroviral drugs is now available to the HIV provider: The CCR5 Antagonists belong to a group of entry inhibitors with a novel mechanism of action. While these antagonists do not directly interfere with any of the steps of HIV replication, they block the CCR5 receptor, one of the co-receptors HIV uses to enter its target cell. Thus CCR5 antagonists are able to prevent infection of the cell and represent a new and unique mechanism for the treatment of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infection of large cell pools; CCR5 antagonists even may be useful tools in the various settings of exposure prophylaxis. Maraviroc is now approved in both the European Union and the United States for the treatment of HIV infection. This is the first medication belonging to the new class of CCR5 antagonists, and the first approval of an orally available drug in a new class since 1996. Aplaviroc, maraviroc, and vicriviroc are small molecule inhibitors of CCR5 that block HIV-1 infection in vitro and reduce plasma HIV-1 RNA in HIV infected subjects by approximately 1.5 log10 copies/mL over 10-14 days when given as single agents. Very limited data is available on the use of CCR5 antagonists in treatment naive patients due to early termination of many trials because of inferior performance or toxicity and at the time of this writing in August 2007 there is only one ongoing non-inferiority trial in the naive patient population. The 48 week interim results of this trial using twice daily maraviroc were reported at the International AIDS Society meeting in July 2007. Maraviroc compared to efavirenz was non-inferior in regards to percentage of subjects reaching viral loads below 400 copies/mL, but not so for the analysis of subjects reaching viral loads below 50 copies/mL. On the other hand maraviroc had a superior side-effect profile, fewer adverse events and a greater increase of CD4 cell count than efavirenz. These data will revitalize the interest in CCR5 antagonists as a treatment option for the treatment-naive patients. In order to be used as first line drugs, CCR5 antagonists face a number of challenges: They will have to be proven to be as potent, durable, safe, and convenient as current available options. Important questions unique to this new class will have to be answered: What are the mechanisms and risks of tropism change? What is the role and needed frequency of tropism testing, and what efficacy is seen in patients with dual-tropic/mixed infection in the long term? Clearly until we have answers to these questions CCR5 antagonists should be reserved for the treatment-experienced patient population with limited treatment options.
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PMID:CCR5 antagonists in the treatment of treatment-naive patients infected with CCR5 tropic HIV-1. 1793 24

The new antiviral CCR5 antagonists have proven to be highly efficient in treatment experienced patient populations with multiple drug failure. Maraviroc is the most advanced compound in clinical development representing this new class of entry inhibitors. The favourable toxicity-, resistance- and pharmacokinetic profile of the drug has been proven in phase III trials in treatment naive and experienced patients. In the latter population, maraviroc had superior antiviral efficacy and immunological activity compared to OBT+placebo alone in the control group. The antiviral responses after 48 weeks were comparable to results obtained from phase III trials with raltegravir and other previous salvage regimens including, darunavir, tipranavir and enfuvirtide. Due to its unique mode of action with exclusive activity against CCR5 tropic strains, viral tropism testing will be mandatory before using CCR5 antagonists in the clinic. The corresponding tests are established and will be further validated. Results from clinical trials indicate that approximately half of the treatment experienced patients will predominantly harbour CCR5 tropic quasispecies and will thus qualify for treatment with CCR5 antagonists. In treatment naive patients maraviroc so far formally failed to prove its non-inferiority to a standard regimen consisting of AZT/3TC+efavirenz after 48 weeks. However, further 96 weeks data will be analysed from this study as well as antiviral efficacy in distinct patient subpopulations. Therefore, it is likely that maraviroc will be recommended in early stages of salvage therapy at present and might replace more inconvenient drugs like enfuvirtide in later lines of therapy. The drug class has also the potential to enter first line therapy but this has to be proven in future trials. Special patient populations like primary HIV infection (PHI), pre- and post exposure prophylaxis, co-infection with tuberculosis and hepatitis B may show special clinical benefit but this is also awaiting confirmation from prospective trials.
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PMID:How will CCR5 antagonists influence the recommendations for the antiretroviral treatment of HIV-1 infection. 1793 25

The concept of CCR5 antagonists introduces an additional molecular target. Maraviroc (MVR) is approved by the FDA for use in HIV-1 infected patients for combination antiretroviral treatment of adults infected with only CCR5-tropic HIV-1 who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Tropism and treatment history should guide the use of MVR. Data from clinical trials show significant efficacy of MVR for patients with pre-treatment and multiple class failure. Additional clinical data show a CD4 reconstitution that is more pronounced than with comparator in treatment naive and in late stage patients even without CCR5-tropic virus indicating patients in earlier stages and even patients without CCR5 testing will benefit from MVR. MVR is not licensed for treatment naive patients but it has a high potential for further development in this patient group. It shows better immunological reconstitution than efavirenz. Pooled safety data from all available trials shows good short term tolerability. Caution is needed in hepatitis co-infection with pre-existing liver damage and in patients with heart failure. Isolates from different geographic regions differ in coreceptor usage. Summarizing knowledge on HIV-1 subtypes and CCR5 tropism shows that in principle all subtypes are susceptible to MVR. However, in subtypes A and D dualtropic and alternative coreceptor use were found. Clinical efficacy in patients from regions with A and D predominance should be studied in future trials. In conclusion, MVR will be of benefit for patients in various treatment situations and regions.
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PMID:Treatment with CCR5 antagonists: which patient may have a benefit? 1793 26

HIV infects target cells by binding of its envelope gp120 protein to CD4 and a coreceptor on the cell surface. In vivo, the different HIV-strains use either CCR5 or CXCR4 as coreceptor. CCR5-using strains are named R5 viruses, while CXCR4-using strains are named X4. X4 viruses usually occur in the later stages. Coreceptor usage is a marker for disease progression. Additionally interest on coreceptors continually raises as a consequence of the development of a new class of antiretroviral drugs, namely the coreceptor antagonists or blockers. These specific drugs block the CCR5 or the CXCR4 coreceptors. So far, the CXCR4 blockers are not allowed to be used in the clinical practice due to their severe side effects. On the other hand, CCR5 blockers are currently in clinical practice, although they can only be administered after a baseline determination of the coreceptor usage of the predominant viral strain. Most of the coreceptor analyses in clinical cohorts have been performed with commercially available phenotypic assays. As for resistance testing of NRTIs, NNRTIs and PIs, efforts have also been made to predict the coreceptor usage from the genotype of the viruses. Different rules have been published based on the amino acid sequence of the Env-V3 region of HIV-gp120, which is known to be the major determinant of coreceptor usage. Among these, the most widely used is the 11/25 rule. Recently, bioinformatics driven prediction systems have been developed. Three of the interpretation systems are freely available via internet: WetCat, WebPSSM, geno2pheno[coreceptor]. All three systems focus on the Env-V3 region and take the amino acid sequence only into account. They learn from phenotypic and corresponding genotypic data. So far, two cohorts have been analyzed with such a genotypic approach and provided frequencies of R5 virus strains that are within the range of those reported with phenotypic assays. For one of the systems, geno2pheno[coreceptor], additional clinical data (e.g. CD4+T-cell counts) or structural information can be used to improve the prediction. Such genotypic systems provide the possibility for rapid screening of patients who may be administered with CCR5 blockers like the recently licensed Maraviroc.
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PMID:Genotypic coreceptor analysis. 1793 27

Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines. The reaction requires 15 mol % (S)-3,3'-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (75-94%) and high enantiomeric ratios (95:5-99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (diastereomeric ratio > 98:2) and enantioselectivities (enantiomeric ratio > 98:2) are obtained in the reactions of acyl imines with crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of Maraviroc, the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of the allylboration reaction including IR, NMR, and mass spectrometry studies indicate that acyclic boronates are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl imine via hydrogen bonding.
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PMID:Asymmetric allylboration of acyl imines catalyzed by chiral diols. 1802 Mar 34


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