Phase III development of T-20 is currently underway, with two pivotal studies in adults, T20-301 in North America and Latin America, and T20-302 in Europe and Australia.

T20-301
Objectives: To assess the safety and efficacy of T-20 90 mg subcutaneous bid plus an optimised background regimen compared to an optimised background regimen alone.
Design: Phase III, randomised, open-label, active-controlled, parallel group, multicenter trial
Patients: 525 antiretroviral-experienced adults or adolescents (³ 16 years of age) with HIV-1 RNA ³ 5,000 copies/ml. Patients must have prior experience (for at least 6 months) and/or prior documented resistance to each of the three classes of approved antiretrovirals, as follows:

                  - nucleoside reverse transcriptase inhibitors (³ 1 member of the class)
                  - non-nucleoside reverse transcriptase inhibitors (³ 1 member of the class)
                  - protease inhibitors (³ 2 members of the class, taken either sequentially or
                    concomitantly for a total of at least 6 months).

Treatments: Patients were randomised in a 1:2 ratio to one of the following:

                  - Optimised background therapy (one-third)
                  - Optimised background therapy plus T-20 90 mg subcutaneous bid (two-thirds)

The background regimen was optimised using baseline HIV genotype, phenotype and clinical history.
Primary endpoint: Change in HIV RNA from baseline at weeks 24 and 48.
Status: Fully recruited, ongoing.

T20-302
Objectives: To assess the safety and efficacy of T-20 90 mg subcutaneous bid plus an optimised background regimen compared to an optimised background regimen alone.
Design: Phase III, randomised, open-label, active-controlled, parallel-group, multicenter trial.
Patients: 525 antiretroviral-experienced adults or adolescents (³ 16 years of age) with HIV-1 RNA ³ 5,000 copies/ml. Patients must have prior experience (for at least 3 months) and/or prior documented resistance to each of the three classes of approved antiretrovirals, as follows:

                  - nucleoside reverse transcriptase inhibitors (³ 1 member of the class)
                  - non-nucleoside reverse transcriptase inhibitors (³ 1 member of the class)
                  - protease inhibitors (³ 1 members of the class, taken either sequentially or
                    concomitantly for a total of at least 3 months).

Treatments: Patients were randomised in a 1:2 ratio to one of the following:

                  - Optimised background therapy (one-third)
                  - Optimised background therapy plus T-20 90 mg subcutaneous bid (two-thirds)

The background regimen was optimised using baseline HIV genotype, phenotype and clinical history.
Primary endpoint: Change in HIV RNA from baseline at weeks 24 and 48.
Status: Fully recruited, ongoing.

T20-305
Objectives: To assess safety and tolerabilty of T-20 in patients with advanced HIV disease who are unable to construct a viable regimen from among approved antiretroviral agents.
Design: A multicenter, open label, uncontrolled, single arm safety study in the US, Canada, Mexico, Brazil, Sweden, UK, Netherlands, Belgium, Germany, France, Switzerland, Spain, Portugal, Italy and Australia.
Patients: Up to 450 HIV-1 infected adults or adolescents (³ 16 years of age) with HIV-1 RNA viral load ³ 10,000 copies/mL and CD4 lymphocyte count £ 50 cells/mm³.
Treatments: T-20 at a dose 90 mg bid administered via subcutaneous injection, in combination with oral antiretroviral drugs for 48 weeks.
Status: ongoing

Paediatric Program
T-20 is currently being studied in two paediatric studies T20-204 (P1005) and T20-310. T20-204 initially investigated the pharmacokinetics of T-20 in 12 children aged 3-12 years administered (15, 30 or 60 mg/m²). T-20 was given by subcutaneous injection at the start of the 48 hour PK study period, and again at 24 hours by intravenous injection. The antiviral activity of T-20 in children is currently being assessed in an extension to the T20-204 study. Fourteen children, including 10 of the 12 individuals from the pharmacokinetic phase of the study have been enrolled to the activity phase of the study. All patients were clinically stable but their existing antiretroviral therapy was failing and all children had viral loads ³ 10,000 copies/mL. Subcutaneous T-20 at a dose of 30 or 60 mg/m² bid was added to the children's failing regimen for 7 days, after which a new background regimen was introduced and T-20 treatment continued. The antiviral activity and safety of T-20 is also being investigated in the ongoing study T20-310 where up to 48 children aged 3-16 years will be dosed at 2mg/kg (up to a maximum of 90 mg) via subcutaneous injection bid for 48 weeks. Patients who have HIV RNA ³ 5000 copies/mL and a maximum of 3 months experience with at least 2 of the 3 currently licensed antiretroviral drug classes will be enrolled.

Clinical Pharmacology Program
Several studies in HIV-infected patients will explore the effect of drugs known to be strong inhibitors of metabolism (e.g. ritonavir) and  a strong inducers of drug metabolism (e.g. rifampin) on T-20 pharmacokinetics. Separately the effect of T-20 on probe substrates of various cytochrome P450 enzymes will be explored (so-called Pittsburgh cocktail study). Further studies will investigate the relationship between injection site and T-20 pharmacokinetics, as well as specific studies to develop a structural pharmacokinetic model for T-20 disposition within the body and its bioavailability. Sparse sampling methods will be employed in the Phase III programme to investigate demographic parameters (e.g. weight or gender) on the pharmacokinetics of T-20.

Clinical experience with T-1249
Following T-20 through clinical development is a second experimental fusion inhibitor, T-1249. The safety, plasma pharmacokinetics and antiviral activity of T-1249 have been investigated in a Phase I/II trial, T1249-101.

ONGOING CLINICAL TRIALS
The Phase I/II clinical development of T-1249 is currently continuing with the following study. Additional studies are expected to begin in 2002.

T1249-101
Objectives: To evaluate the short-term safety, efficacy and pharmacokinetics of different doses of T-1249 administered to HIV-1-infected patients
Design: 14-day, open-label, monotherapy study
Patients:  72 participants with HIV RNA ³ 5,000 copies/ml, no antiretroviral  therapy for at least 2 weeks prior to the screening visit, and no active opportunistic infections.
Treatments: Treatment comprised 14 days of monotherapy with T-1249 at doses ranging from 6.25 mg qd to 25 mg bid.
Status: Ongoing.
Reference: Eron J, Merigan T, Kilby M, Yangco B, Gleavy J, Rusnak P, Dimassimo B, Smith R, Baker B, Duff F, Drucker J, Matthews T, Hopkins S for the T1249-101 Study Group. A 14-day assessment of the safety, pharmacokinetics, and antiviral activity of T-1249, a peptide inhibitor of membrane fusion. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, Illinois,  USA, 2001; Abstract 14.