TMC114 and Other Investigational Drugs for Salvage Therapy

It is well known that highly active antiretroviral therapy (HAART) is effective for HIV positive people initiating treatment, and that suppression of HIV replication is durable in those who can tolerate potent multidrug anti-HIV therapy over long periods. In a recent study, the rate of viral breakthrough on treatment was 3.6 per 100 person-years, equivalent to one individual with viral breakthrough per 27.8 person-years of follow-up. (A person-year is a shorthand term used by epidemiologists to make comparisons.) This low rate of viral rebound and results from other research suggest that if viral suppression is achieved with initial treatment, and if adherence to therapy can be maintained, the chances of treatment failure are minimal. Yet antiretroviral therapy may still fail despite the availability of some 18 anti-HIV drugs, and the need for salvage, or "rescue," regimens remains urgent.

Although there have been concerns regarding drug development and progress in moving experimental candidates toward regulatory approval, new findings were presented for several investigational agents that show promise as part of future salvage regimens at the 10th Conference on Retroviruses and Opportunistic Infections, held February 10--14, 2003, in Boston. Speaking at the conference, John Mellors, MD, a virologist from the University of Pittsburgh, referred to the number of new compounds in the pipeline as a "bumper crop." Several of these agents are being investigated as therapies for treatment-experienced people with resistant virus.

TMC114

TMC114 is a second-generation protease inhibitor (PI) from Tibotec-Virco, a Belgian pharmaceutical company owned by Johnson and Johnson. The drug is designed to be active specifically against virus with PI-resistant mutations. Previous in vitro (laboratory) work has shown that TMC114 has potent activity against both wild-type (nonmutated) and PI-resistant HIV. Ritonavir (Norvir) enhances the effects of TMC114 in vivo (in humans), and coadministration of ritonavir may allow lower doses of TMC114 to be used. At the Retrovirus conference one oral and two poster presentations provided the latest in vitro and clinical results for this promising new compound.

The first clinical results for TMC114 in people with HIV were presented by Keikawus Arasteh, MD, from Vivantes Auguste-Viktoria-Klinikum in Berlin. In an open, randomized, two-week Phase II study, TMC114 was evaluated in 50 HIV positive participants who had previously taken multiple PIs and whose current PI-containing regimens were failing. Mean (average) baseline plasma viral load and CD4 cell counts were 20,000 copies/mL and 297 cells/mm³, respectively. The mean number of primary PI mutations per participant was six, and nearly half had virus resistant to all available PIs. TMC114 plus low-dose ritonavir at one of three different dosages--300 mg/100 mg twice daily, 600 mg/100 mg twice daily, or 900 mg/100 mg once daily--was substituted for the failing PI in the regimens of 38 of the subjects, while 12 continued their current regimens; no other antiretrovirals were changed.

After 14 days an intent-to-treat analysis (which included all subjects according to the original randomization, even if they later switched therapy or dropped out) showed that TMC114/ritonavir reduced viral load by 90% in 70--90% of treated participants, depending on the dosage used. The twice-daily regimens outperformed the once-daily regimen. Decreases in viral load from baseline ranged from 0.47 to 2.49 log (mean of 1.35), and almost all participants (97%) who received TMC114/ritonavir had at least a 0.5 log (70%) drop in viral load. (See sidebar on page 15 for an explanation of logs.)

The most commonly reported adverse events were gastrointestinal (GI) symptoms; 32% of the participants experienced diarrhea--a much lower percentage than seen when TMC114 is given at higher dosages without ritonavir. Serious toxicities seen in the study were (reversible) liver inflammation in one person and severe liver enzyme elevations in five others receiving a TMC114/ritonavir regimen. Two people discontinued treatment, one due to GI discomfort and the other due to severe rash.

Two poster presentations at the conference provided new data on TMC114's in vitro potency against resistant virus and its clinical pharmacokinetics (action in the body) and safety when coadministered with ritonavir. The laboratory study tested TMC114 against HIV strains with mutations conferring resistance to the PIs ritonavir, saquinavir (Fortovase), indinavir (Crixivan), nelfinavir (Viracept), and amprenavir (Agenerase). The results showed that TMC114 not only blocked the infection of human CD4 cells by resistant virus, but also was active against multi-PI--resistant virus from people who had no response to any existing antiviral regimens. Analysis of the interaction of TMC114 with the HIV protease molecule revealed that TMC114 differs from existing PIs--perhaps due to the compound's highly flexible and adaptive nature--which may account for its potency against resistant virus.

The second poster presented a study of different doses of TMC114 given with and without ritonavir to healthy, HIV negative volunteers for 14 days. The results showed that the minimum TMC114 concentrations and drug exposure over a 24-hour period were substantially increased when TMC114 was given with low-dose ritonavir--even when administered once daily at lower doses--compared with TMC114 used alone twice daily. The frequency of adverse events was reduced, however, in the volunteers who received TMC114 plus ritonavir compared with those who received higherdose TMC114 alone. For those taking TMC114 alone, GIrelated adverse events included diarrhea in 78%, vomiting in 17%, and nausea in 14%. For those taking TMC114/ritonavir, diarrhea was reported in 30% and nausea in 7.5%. These results suggest that the adverse effects of TMC114 may be lessened without any loss of potency through the coadministration of low-dose ritonavir.

The GI effects of TMC114 are largely attributable to a substance in its current formulation, polyethylene glycol. According to Richard Hoetelmans, PhD, the study's lead investigator, a tablet formulation without polyethylene glycol is being investigated, but results are not expected until 2004. The most effective and safest formulation and dose of TMC114 remain to be determined.

Overall, the results of these studies show that TMC114 used with low-dose ritonavir given either once or twice daily has promise as a new agent to treat PI-resistant HIV, and that further clinical testing should be pursued. More will be known about the future of this drug once the results of the planned 24-week trials using the tablet formulation are available. With PI resistance continuing to be a cause of treatment failure, these results will be closely watched.

Other Novel Investigational Agents for Salvage Therapy

New agents in development from existing antiretroviral drug classes appear to offer advantages over those currently in clinical use, such as less complex treatment regimens, increased efficacy against resistant virus, and less toxicity. However, cross-resistance within the PI and non-nucleoside reverse transcriptase inhibitor (NNRTI) classes may limit their impact, especially when compared with investigational drugs that act against new viral targets.

Oral and poster presentations on 44 different experimental anti-HIV compounds were presented at the Retrovirus conference. Of these, 32 involve novel approaches that are not related to any of the first three antiretroviral drug classes (nucleoside reverse transcriptase inhibitors [NRTIs], NNRTIs, and PIs); 15 are genetic or immune-based therapies. Below are brief summaries of the findings presented at the conference for several agents that may have potential as future treatment options for salvage therapy. (Note: none of the new genetic therapies, which are at a very early stage of development, are included.)

Entry Inhibitors

Twelve presentations provided new data on experimental entry inhibitors, which include binding and fusion inhibitors. Agents in this class attempt to block HIV from entering host cells. The first drug in this class, T-20 (enfuvirtide, Fuzeon), was granted U.S. approval in March for use with other antiretrovirals in treatment-experienced people with persistent viral load despite ongoing anti-HIV therapy-- in other words, as part of a salvage regimen. As with other antiretrovirals, however, resistance to T-20 has been observed. One study presented at the conference showed a mean 21-fold loss of susceptibility in those whose T-20 treatment failed. The development of new entry inhibitors remains a priority, and three of the more promising agents in this class are discussed below.

T-1249

The fusion inhibitor T-1249 has a structure similar to that of T-20. Now in Phase II clinical trials, T-1249 appears to have 2 to 100 times greater potency than T-20, and is active against T-20--resistant virus. Like its predecessor, T-1249 inhibits fusion of HIV with host cells by binding to the gp41 protein on the virus' surface, but at a slightly different location, which is believed to account for T-1249's activity against T-20--resistant virus. Thus, it appears that T-1249 may be a useful option for some people whose HIV has developed resistance to T-20.

The results from a planned interim analysis of a trial sponsored by Roche/Trimeris, the pharmaceutical partnership developing T-1249, were presented at the conference. The study evaluated T-1249 (192 mg once daily) in 25 participants taking failing regimens containing T-20 (i.e., two consecutive plasma viral load measurements between 5,000 and 500,000 copies/mL). At the time of switching from T-20 to T-1249, mean viral load was 100,000 copies/mL. Twentyfour of these heavily pretreated participants had T-20--resistant virus, as revealed by genotypic resistance testing.

The interim results showed that in the first 25 participants who completed the ten-day study, approximately twothirds experienced decreases in viral load of at least 1 log (90%). No subjects discontinued the study, and no serious adverse events considered related to T-1249 were reported. The results also showed that the longer people received T-20 after the detection of virological failure, the less response they had to T-1249, most likely due to the increasing development of cross-resistance during persistent viral replication. This suggests that T-20 should be stopped as soon as possible if resistance develops in order to preserve the benefit of T-1249.

Like T-20, T-1249 must be given via subcutaneous (under the skin) injection. It appears that T-1249 injections can be given once daily, compared with twice daily for T-20, but four separate injections will be required with each administration.

TNX-355

Another entry inhibitor in clinical trials is the anti-CD4 monoclonal antibody TNX-355 (formerly Hu5A8), produced by Tanox. These antibodies (immune system proteins that recognize foreign substances) are genetically engineered to attach to the CD4 receptors on the surface of T cells, thereby preventing the entry of HIV into the host cell.

TNX-355 is currently in Phase I testing. Results of a short-term, single-dose, dose-ranging study of TNX-355 in 30 treatment-experienced HIV positive participants, 19 of whom were receiving a failing regimen, were presented at the conference by Daniel Kuritzkes, MD, a virologist at Brigham and Women's Hospital and Harvard Medical School in Boston. The study found that decreases in HIV plasma viral load occurred at all doses of TNX-355 tested (1, 3, 10, and 25 mg/kg) and, as expected, the higher doses were associated with better virological response (lower viral load). Ten of the 12 participants who received the higher doses had significant drops in viral load, with peak reductions occurring 2--3 weeks after the single dose. Viral load decreased as much as 97% in some participants. No decrease in the number or function of CD4 cells was detected, and no serious adverse events were noted.

Like the fusion inhibitors T-20 and T-1249, TNX-355 also must be given by injection (although T-20 and T-1249 are given subcutaneously, while TNX-355 is infused intravenously, or directly into a vein). However, unlike the Roche/Trimeris drugs, which are administered daily, TNX-355 may need to be given only once every 2--3 weeks. The optimal dose and the duration of TNX-355's effects remain to be determined, and a multiple-dose study is planned.

UK-427,857

in vitro and early clinical results were presented at the Retrovirus conference for UK-427,857, an entry inhibitor that works by blocking HIV from attaching to a coreceptor called CCR5 that the virus uses to enter many host cells. The compound is currently in Phase I clinical testing. The in vitro results showed that UK-427,857 has potent activity against the HIV subtype most common in the U.S. (subtype B), as well as those commonly found in other parts of the world (subtypes A, C--G, J, and O), including Africa and Asia.

Preliminary clinical data also appear encouraging. Results of a dose-ranging, pharmacokinetic study in healthy, HIV negative volunteers showed that UK-427,857 can be given orally, is rapidly absorbed, and has a good safety profile--at least so far. Importantly, UK-427,857 does not seem to promote heart problems. (In early studies it appeared that some other CCR5 blockers--such as Schering- Plough's SCH-C--might increase the risk of irregular heartbeat.) As with many other investigational agents in early trials, the dose of UK-427,857 that will be used in future efficacy and safety studies has not yet been determined.

Integrase Inhibitors

The HIV integrase enzyme is responsible for inserting the virus' genetic material into the host cell's DNA (known as integration), thereby employing the cell's machinery for viral replication. Several experimental compounds inhibit this step in the viral lifecycle. Although no clinical data were presented at the Retrovirus conference on the two agents furthest along in development--L-708,906 and S-1360, both of which are diketo (or diketobutanoic) acids currently being tested in humans--results from in vitro studies show that there may be a significant potential for cross-resistance among the diketo compounds, and that other types of integrase inhibitors with distinct resistance profiles should also be investigated.

Based on data presented at the conference, one solution may be the pyranodipyrimidine (PDP) integrase inhibitors, which are structurally different from the diketo compounds. Early findings with V-165, a PDP agent being developed by the Rega Institute in Belgium, suggest that this compound inhibits both the reverse transcription step and the HIV integration step--a level of activity beyond that exhibited by the two leading integrase inhibitor candidates. In addition, V-165 was reported to be active in vitro against viral strains that are resistant to diketo compounds. These results are promising, but preliminary.

Budding Inhibitors

Early preclinical results from a study of PA-457, an agent from a new class of antiretrovirals called budding inhibitors, were presented at the conference by researchers from Panacos Pharmaceuticals. PA-457 appears to interrupt later stages of the HIV lifecycle, when newly produced viral proteins are packaged into new virus particles (virions) as they leave the infected host cell through the cell membrane-- a process called budding. How exactly PA-457 inhibits this process is unknown.

In laboratory tests PA-457 showed potent activity against all HIV isolates, including those highly resistant to NNRTIs and PIs. The compound was also found to act synergistically (with enhanced effects) with AZT (zidovudine, Retrovir), nevirapine (Viramune), and indinavir, which together represent the first three major classes of approved antiretrovirals.

Finally, PA-457 was orally bioavailable (able to be taken by mouth) in an animal model. Based on study results to date, the manufacturer intends to proceed with further development of this compound.

Conclusion

Effective and less toxic salvage therapy options for people with HIV remain a pressing need, as existing drug regimens continue to fail due to resistance and less-than-optimal adherence, with its ensuing loss of potency. Thus, the ongoing development of second-generation antiretroviral agents, including those that interfere with new steps in the HIV lifecycle, is crucial for broadening and improving treatment for those with limited therapeutic options. Although history indicates that most of the experimental compounds presented at the Retrovirus conference will never attain FDA approval, it is heartening to see so much interest and progress on the part of the pharmaceutical industry in identifying and developing novel agents.

Selected Sources

Abel, S. and others. Pharmacokinetics of single and multiple oral doses of UK- 427,857--a novel CCR5 antagonist in healthy volunteers. 10th Conference on Retroviruses and Opportunistic Infections (CROI). Boston, MA. February 10--14, 2003. Abstract 547.

Arasteh, K. and others. First clinical results on antiretroviral activity, pharmacokinetics, and safety of TMC114, an HIV-1 protease inhibitor, in multiple PI-experienced patients. 10th CROI. Abstract 8.

Debyser, Z. and others. Pyranodipyrimidines: A new class of HIV integrase inhibitors that block viral replication in cell culture. 10th CROI. Abstract 9.

Fikkert, V. and others. Distinct antiviral resistance profiles for the authentic HIV integrase inhibitors: the diketo compounds L-708,906 and S-1360 and the pyranodipyrimidine V-165. 10th CROI. Abstract 556.

Greenberg, M.L. and others. Enfuvirtide (T-20) and T-1249 resistance observations from Phase II clinical trials of T-20 in combination with oral antiretrovirals and a Phase I/II dose-ranging monotherapy trial of T-1249. Antiviral Therapy 7(suppl 1): S106--S107. 2002. Abstract 128.

Hoetelmans, R. and others. TMC114, a next generation HIV protease inhibitor: Pharmacokinetics and safety following oral administration of multiple doses with and without low doses of ritonavir in healthy volunteers. 10th CROI. Abstract 549.

Koh, Y. and others. TMC114 (UIC96017): A novel nonpeptidic protease inhibitor potent against multi-PI resistant HIV in vitro. 10th CROI. Abstract 553.

Kuritzkes, D.R. and others. Safety and preliminary anti-HIV activity of an anti-CD4 mAb (TNX-355; formerly Hu5A8) in HIV-infected patients. 10th CROI. Abstract 13.

Miralles, G.D. and others. T-1249 demonstrates potent antiviral activity over 10 day dosing in most patients who have failed a regimen containing T-20 (ENF): planned interim analysis of T1249-102, a Phase I/II study. 10th CROI. Abstract 14lb.

Wild, C. and others. PA-457 is a small molecule inhibitor of HIV-1 budding/maturation that potently inhibits replication of virus isolates resistant to all classes of approved drugs. 10th CROI. Abstract 14.