Encouraging Data at 13th CROI on Novel New HIV Protease Inhibitor TMC 114 and Unique Non Nucleoside TMC 125

By Ronald Baker, PhD

TMC114 is an HIV protease inhibitor (PI) that is potent against wild type and PI-resistant HIV that is administered with low-dose ritonavir (TMC114/RTV). The drug currently is in Phase 3 clinical trials and a TMC 114 Early Access Program (EAP) is ongoing in the US. EAPs allow drug manufacturers to provide promising experimental drugs for serious or life-threatening illnesses free to patients without other viable treatment options prior to FDA approval of these agents.

Tibotec, the drug’s manufacturer, recently filed for approval of TMC 114 by both the US and European drug regulatory agenecies (US FDA and EMEA, respectively). Both submissions are based on the efficacy and safety results of the 24-week dose-finding phase two randomized controlled studies, known as POWER 1 and POWER 2, and supportive data from a non-randomized open label trial, POWER 3.

Understanding the Factors Predicting Virologic Response with TMC114

S De Meyer and colleagues presented new data on Tibotec’s experimental protease inhibitor (PI) TMC 114 at the 13^th CROI in Denver last week [1]. The results of resistance analyses of POWER 1, 2 and 3 showed that the TMC114 baseline fold change in EC₅₀ (FC) was the strongest predictor of antiviral activity with TMC114 (Abstract 157). 

A diminished TMC114 response was observed in the presence of multiple baseline PI-resistance-associated mutations (³10) together with one or more specific mutations. Nonetheless this response was still greater than that observed in the control groups in POWER 1 and 2.

The authors conclude, “TMC114/r 600/100 mg twice daily showed significant efficacy benefits over CPI, independent of baseline CPI susceptibility. In a background of a substantial number of PI-resistance mutations, particular additional mutations may be associated with reduced TMC114 susceptibility.”

Pharmacokinetic/ Pharmacodynamic Analyses of POWER 1 and 2 Studies

In a 24-week pharmacokinetic/ pharmacodynamic analyses of the POWER 1 and 2 studies [2], Tibotec researchers compared with control PI (CPI) regimens, 4 TMC114/RTV doses: (1) 400/100 mg once daily, (2) 800/100 mg once daily, (3) 400/100 mg twice daily, and (4) 600/100 mg twice daily). An optimized background regimen consisting of nucleoside reverse transcriptase inhibitors ± enfuvirtide (EFV) [Fuzeon] was used in each treatment arm.

The results showed there was no clear relationship between TMC114 pharmacokinetic/ parameters and efficacy parameters in patients with TMC114 fold change values >40, nor in patients with TMC114 fold change values £4. Also, there was no apparent relationship between TMC114 pharmacokinetic parameters and safety measures.

In addition, analyses of the POWER 1 and 2 studies confirmed that baseline TMC114 FC rather than exposure influenced the virologic response to TMC114.

In conclusion, the authors write, “Pharmacokinetic/pharmacodynamic relationships for TMC114 provide evidence to support the recommendation of the 600/100 mg twice daily dosing regimen in treatment-experienced HIV-1-infected patients.”

First Results of PI TMC 114 and NNRTI TMC 125 in Combination

Marta Boffito, MD, PhD, of Chelsea and Westminster Hospital, London, presented a late-breaker poster at the 13^th CROI on the first clinical results of virologic response to TMC 114 and TMC 125 in combination [3].

This pharmacokinetic (PK) study in 10 HIV patients (N=10) with substantial PI and NNRTI resistance revealed that eight out of the ten patients achieved an undetectable viral load

(<40 copies per ml HIV-RNA) by week twelve. Furthermore, all patients attained at least a 2 log₁₀ decrease in HIV-RNA at 12 weeks.

In addition to TMC 125 and ritonavir-boosted TMC 114, patients received two or more NRTIs. Two patients used the entry inhibitor enfuvirtide (Fuzeon) for the first time. No significant PK interaction was observed. “These preliminary results are encouraging and suggest that the combination of these two investigational antiretrovirals may provide a new treatment option in heavily treatment-experienced patients such as these,” said Dr. Boffito.

The authors conclude, “No significant pharmacokinetic interaction between TMC 114 and TMC 125 was observed. The combination was well tolerated and showed impressive short-term efficacy against 3-class resistant HIV. Further studies of this combination are warranted.

Note: TMC 125 is being studied in combination with TMC 114 in the placebo-controlled phase 3 studies, DUET 1 and 2, which are currently enrolling in the US, Europe and other countries.

TMC 125 Activity against NNRTI-resistant HIV

J Vingerhoets presented the impact of baseline resistance on the virologic response to TMC125 from study TMC125-C223 [4].  In the presence of one or two NNRTI mutations, viral load reductions of 1.65 log₁₀ and 1.00 log₁₀ respectively were observed at 24 weeks with TMC 125 800mg twice daily treatment in combination with an optimized background regimen compared with a 0.19 log₁₀ drop for the control group on best available regimen from licensed agents.

This presentation follows study results presented at the 45^th ICAAC in Washington, DC, in December 2005 that looked at the 24-week primary efficacy and safety results. The most common adverse events (AEs) were diarrhea and rash (20% each for the TMC 125 groups compared with 15% and 8% for the active control group). Overall, 23% of TMC 125 and 18% of control patients reported at least one SAE.

Further analyses of the TMC 125-C223 results, including the resistance profile of TMC 125, are ongoing.

The authors conclude, “This analysis shows that TMC 125 retains activity in the presence of multiple NNRTI mutations where current NNRTI are not expected to be effective.

Additionally, a study by Scholler and others investigating the interactions between TMC 125 and the PI tipranavir (Aptivus) showed a significant decrease of TMC 125 exposure [5].

02/17/06

References

1. S De Meyer and others. Effect of Baseline Susceptibility and On-treatment Mutations on TMC114 and Control PI Efficacy: Preliminary Analysis of Data from PI-experienced Patients from POWER 1 and POWER 2. 13th Conference on Retroviruses and Opportunistic Infections, February 5-8, 2006. Denver, Co. Abstract 157.

2. V Sekar and others. Pharmacokinetic/Pharmacodynamic Analyses of TMC114 in the POWER 1 and POWER 2 Trials in Treatment-experienced HIV-infected Patients. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, Co. Abstract 639b.

3. M Boffito and others. Pharmacokinetics and ART Response to TMC114/r and TMC125 Combination in Patients with High-level Viral Resistance. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, Co. Abstract 575c.

4. J Vingerhoets and others. Effect of Baseline Resistance on the Virologic Response to a Novel NNRTI, TMC125, in Patients with Extensive NNRTI and PI Resistance: Analysis of Study TMC125-C223. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, Co. Abstract 154.

5. M Harris and others. Pharmacokinetics and Safety of Adding TMC125 to Stable Regimens of Saquinavir, Lopinavir, Ritonavir, and NRTI in HIV⁺ Adults. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, Co. Abstract 575b.