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  8th European Conference on Clinical Aspects and treatment of HIV-Infection (ECCATHI)
Athens, Greece - October 2001
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Entry Inhibitors: T-20 (adults & children), T-1249 (early data in adults)
Written by Jules Levin
  The development of this new class of drugs is an important development for patients with resistance to the currently available HIV drugs. Patients with resistance to the current drugs are not expected to have resistance to these entry inhibitors, since they are a new class of drugs. However, T-20 and T-1249 are administered by subcutaneous injection. Recently, PMPA was approved by the FDA and this drug also should be effective for many individuals with resistance to currently available NRTIs. Taken together, the development of these 2 drugs (T-20 and PMPA) offers advances in treating HIV resistance. Unfortunately, both drugs are not available at the same time yet. PMPA was just approved and is available but T-20 is still in phase 3 study.
Frank Duff from Roche reported an update on T-20 and T-1249, new entry inhibitor drugs for treating HIV, at the Athens 8th ECCATHI Conference. HIV fusion is the process by which HIV binds to and enters CD4 cells for the purpose of using the CD4 cell as a manufacturing plant for new HIV particles, which in turn are churned out by the CD4 cell to infect additional CD4 cells. Researchers are trying to develop a whole new class of HIV drugs called entry inhibitors. T-20 and T-1249 are the furthest along in development. Entry inhibitors prevent HIV from entering the CD4 cell. While currently available HIV drugs such as NRTIs, protease inhibitors, and NNRTIS, prevent HIV from reproducing once inside the CD4 cell. Much of the data reported in this presentation is not necessarily new.
Duff reported from study TRI-001 how T-20 monotherapy reduced HIV-RNA viral load about 1.5 log after 18 days in an early study in persons who were treatment-naive (100 mg twice daily administered by IV). T-20 is administered by subcutaneous injection similarly to insulin and interferon. The key phase 3 study for T-20 is ongoing now and I believe its fully enrolled or close to it. Upon completetion, Roche will be submitting the results to the FDA for commercial approval. A small expanded access program has just been announced by Roche.
T20-205 was a safety evaluation and secondarily an assessment of antiviral activity for T-20. Patients received 50 mg twice daily and patients were treatment experienced and rolled over from previous T-20 studies. Regimens were individualized based on treatment history and genotype. Baseline CD4s were 90 and viral load 100,000 copies/ml. Patient had much ART experience: 97% PI experienced; 79% experience with all 3 drug classes; average number of previous drugs=9; on avarage study patients were taking 5 ART drugs.
Duff reported there were no discontinuations attributed to T-20 related adverse events. 71% had mild to moderate injection site reactions. 21% had Grade 3 events possibly related to T-20. 10% had serious adverse events possibly related to T-20. Using the stringent ITT (non-completer=failure) analysis (n=70) after 48 weeks, Duff reported that 33% of the study patients had <50 copies, between 50-400 copies/ml, or >1 log reduction in viral load but still had >400 copies/ml. 13% had <50 copies/ml. 10% had >50 but <400. And 10% had >1 log reduction in viral load from baseline but still had >400. Duff reported on 41 patients who completed the 48 weeks of the study, that is were able to stay on study drugs for 48 weeks. Presumably the ITT analysis excluded study discontinuations. In this less stringent analysis, 56% (n=41) of the patients had <50, >50 but <400, or >1 log viral load reduction. 22% had <50 copies/ml, 17% had >50 but <400, and 17% had >1 log viral load reduction.
PACTG 1005 was a study of T-20 in children. T-20 30 mg/m2 or 60 mg/m2 subcutaneously were added to stable but failing background therapy for 7 days then background ART was optimized. This was an open-label, ascending dose study looking at single and multiple doses for safety and antiviral activity.
The study included13 treatment experienced children age 4-12 with average viral load of 29,000 copies/ml and CD4 count of 623. Duff reported that the pharmacokinetic/pharmacodynamic (PK/PD) targets were achieved with 60 mg mg/m2 of T-20. T-20 was safe & well tolerated up to 8 weeks. 10 of 13 patients achieved 0.7 log reduction in viral load by day 7. 9 of the 13 patients maintained response of > 1 log at 8 weeks with T-20 and optimized background.
This is a second generation entry inhibitor from Roche/Trimeris. From early research it appears to be more potent than T-20 and it has been reported to be effective against most HIV isolates tested that were resistant to T-20. T-1249-101 was a 14-day open-label study of the safety, pharmacokinetics, and antiviral activity of monotherapy subcutaneous injections of T-1249. 63 HIV+ adults received dose escalation in once or twice per day regimens: 6.25 mg once daily, 12.5 mg once daily, 25 mg once daily; or, 6.25 mg twice daily, 12.5 mg twice daily, 25 mg twice daily.
At baseline, viral load was 5.3 log (well over 100,000 copies/ml). Average CD4 count was 121. The patients in this study were very treatment-experienced. 98% had previous ART treatment: about 90% experienced with all 3 drug classes. On average the patients had used 10 ART drugs previously. And 52% of patients had mutations to all 3 classes of drugs. Duff reported that the exposure dose was proportional from 6.25 mg to 50 mg/day. The once daily and twice daily AUC (drug levels in the blood) were comparable at a given daily dose. The most common adverse events were: injection site reaction (40%), headache (11%), pyrexia (8%), dizziness (8%), diarrhea (6%). 2 treatment-related serious adverse events were reported by 2 patients: hypersensitivity reaction and neutropenia. Duff reported of the 194 treatment-related adverse events (71%) seen no apparent pattern within or across patient groups were seen and no relationship was seen between frequency of dose and dose.
Duff reported that the best viral load response may not have been reached and higher doses will be explored. Using the highest dose of T-1249 (total daily dose of 50 mg/day), the average viral load reduction was about 1.3 log after 14 days. There was a dose response meaning as dosing increased from the lower dose regimens viral load reductions increased to the 1.4 log level with the highest dose regimen used in study (equivalent to 50 mg/day).