Substantial progress continues to be made in the arena of antiretroviral drug development. PRN is again proud to present its annual review of the experimental agents to watch for in the coming months and years. This year’s review is based on a lecture by Dr. Roy M. Gulick, a longtime friend of PRN, and no stranger to the antiretroviral development pipeline.
To date, twenty-two antiretrovirals have been approved by the Food and Drug Administration (FDA) for the treatment of HIV infection. In addition to the development of new drugs and drug classes with unique potency advantages, a number of older antiretrovirals have been reformulated to allow for more simplified dosing. Examples include fosamprenavir (Lexiva) tablets, replacing the amprenavir (Agenerase) liquid capsules; liponavir/ritonavir (Kaletra) tablets, replacing the liquid capsules; and the new tablet formulation of saquinavir (Invirase), replacing the 200-mg capsules of Invirase and the need for Fortovase. Additionally, the development of fixed-dose combination tablets have considerably improved treatment acceptance. For the first time, a widely used complete drug regimen is available to take as one pill once per day. Atripla, a fixed-dose combination drug containing daily doses of tenofovir (Viread), emtricitabine (Emtriva), and efavirenz (Sustiva), was approved by the FDA on July 12, 2006.
Even with increasingly simplified treatment regimens, challenges still remain in finding products with minimal toxicity and optimized resistance profiles. To achieve optimal viral suppression, there is also a need for agents that penetrate viral reservoirs and target new portions of the HIV lifecycle. Fortunately, the antiretroviral drug pipeline contains several promising agents that may address these needs.
A summary of these agents is shown in Table 1. Some of these are new members of existing drug classes, including reverse transcriptase inhibitors and protease inhibitors, and some are members of new drug classes, such as integrase inhibitors.
| NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) | Top of page |
Dr. Gulick described two NRTIs in development: dexelvucitabine, formerly Reverset and developed by Incyte, and apricitabine, being developed by Shire Pharmaceuticals. There is, unfortunately, little need to review the development of dexelvucitabine. On April 3, 2006, Incyte announced that it had discontinued all clinical trials of the drug, due to a high frequency (>15%) of grade 4 hyperlipasemia, a marker of pancreatic inflammation (Incyte, 2006).
Apricitabine
Apricitabine is a cytosine analogue that, in vitro, is active against both wild-type virus and HIV with reverse transcriptase harboring the M184V mutation. However, it is not active against HIV containing the RT mutations K65R, V75I, and Q151.
Apricitabine has a bioavailability of 85% to 90%, with linear pharmacokinetics and a long extracellular half-life of approximately 10 hours (Zhu, 2003). During apricitabine’s development, a serious drug interaction with lamivudine (Epivir) was noted. Although the plasma concentrations of apricitabine were unaffected by coadministration of lamivudine, the intracellular concentrations of apricitabine were reduced by approximately sixfold. Additionally, the 50% inhibitory concentration (IC50) of apricitabine against HIV with the M184V mutation was increased 2- to 4-fold in the presence of lamivudine (Bethell, 2004). Taken together, these data suggest that coadministration of apricitabine with lamivudine will be an unlikely option.
Dr. Gulick reviewed a phase I placebo-controlled, dose-ranging study involving 62 HIV-positive, treatment-naive volunteers with HIV-RNA levels between 5,000 and 100,000 copies/mL and CD4+ counts above 250 cells/mm3. The patients were randomized to six doses of apricitabine given once or twice daily, or a matched placebo. Dose-dependent viral load reductions of up to 1.6 log10 copies/mL were seen at the end of 10 days. Apricitabine was well tolerated with no development of resistance mutations over the short 10-day study (Cahn, 2006). Phase II studies are currently under way.
Integration of viral DNA into the host genome is a complex, 3-step process (see Figure 3). The HIV integrase removes two deoxynucleotides at the end of the viral DNA strand and subsequently ligates it to the host chromosomal DNA. The viral-specific integrase enzyme can be targeted much like HIV reverse transcriptase or HIV protease. The group of integrase inhibitors currently in clinical development (MK-0518 and GS-9137) interferes specifically with the last step of the integration process: strand transfer.
MK-0518
Merck’s MK-0518 is primarily metabolized by glucuronidation, meaning that drug interactions are expected to be minimal. In phase I 10-day, monotherapy studies involving treatment-naive patients, MK-0518 resulted in a reduction of 1.7 to 2.2 log10 copies/mL in HIV-RNA (Morales-Ramirez, 2005).
In a subsequent phase II study, 167 heavily treatment-experienced patients were randomized to an optimized background regimen plus either placebo or one of three daily doses of MK-0518: 200, 400, or 600 mg (Grinsztejn, 2006). In preliminary results at 16 weeks, the placebo group had an average viral load reduction of 0.5 log10 copies/mL, while the groups that added the integrase inhibitor had a reduction of greater than 2 log10 copies/mL in viral load. Additionally, nearly 60% of patients on the three MK-0518 arms of the trial achieved viral load reduction to less than 50 copies/mL at week 16.
Twenty-four–week data from a 48-week, phase II study were reported at the XVI IAC by Dr. Martin Markowitz of the Aaron Diamond AIDS Research Center (ADARC) (Markowitz, 2006). The study enrolled 198 treatment-naive patients. The patients were randomized to one of four MK-0518 doses—the same doses explored in the phase I study—or efavirenz. All patients also received tenofovir (Viread) and lamivudine.
After 24 weeks of therapy, 85% to 95% of patients receiving an MK-0518–based regimen had viral loads below 50 copies/mL, compared with 92% in the efavirenz treatment group. CD4+ counts, ranging from 271 to 314 cells/mm3 at baseline, increased in all patients after 24 weeks of treatment. Among patients in the MK-0518 groups, CD4+ counts increased by 139 to 175 cells/mm3. In the efavirenz group, CD4+ counts increased by 112 cells/mm3. Neither the HIV-RNA differences nor the CD4+ cell count differences between the MK-0518 treatment groups and the efavirenz treatment group were statistically significant.
Thus far, treatment with MK-0518 or efavirenz seems to be well tolerated. Nausea, dizziness, and headache appear to be the most frequently reported adverse effects. The only possible treatment-related toxicity of concern was in a patient in the 600-mg MK-0518 group who discontinued therapy due to substantially increased liver enzymes.
Phase III trials are currently enrolling, and an Expanded-Access Program (EAP) has been available since September of 2006. More information on the EAP can be obtained at www.earmrk.com.
GS-9137
GS-9137, being developed by Gilead, also reported early clinical results. This compound is metabolized by the hepatic CYP3A enzyme system. Since ritonavir increases GS-9137 exposure 20-fold, these two agents are being developed together. A phase I study, involving 40 patients who were either treatment naive or treatment experienced, randomized subjects to receive one of four doses of GS-9137 monotherapy, one dose of ritonavir-boosted monotherapy, or placebo for 10 days (DeJesus, 2006). The GS-9137/ritonavir 50-/100-mg, once-daily dose performed best with a reduction of greater than 2 log10 copies/mL in HIV-RNA at day 11, and a substantial antiviral effect lasting between seven and 14 days following treatment discontinuation. This compound is currently in phase II clinical trials.
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