Fusion inhibitors are a new class of anti-HIV therapy that targets the earliest part of HIV's lifecycle, its entry into the human cell. Unlike the reverse transcriptase inhibitors (nucleoside, non-nucleoside, and nucleotide) or protease inhibitors which attack HIV already inside the cell as it attempts to reproduce itself, fusion inhibitors prevent HIV’s entry in the first place. Since HIV specifically targets the human CD4 immune cell, blocking fusion could mean greater protection of the immune system. And by working outside the cell, fusion inhibitors minimize the potential for side effects associated with anti-HIV therapy.

About T-20

T-20 is a synthetic, 36 amino acid peptide that mimics a segment of the HIV gp41¹ that, with gp120, forms a key portion of the HIV-to-cell binding complex. gp41 is the "stinger" that penetrates the cell membrane and brings the virus into contact with the cell membrane in such a way that fusion can occur. Once gp120 latches onto the cell's receptor, it unfolds to expose gp41. T-20 binds to gp41, preventing it from changing its shape. Without this change of shape, gp41 cannot penetrate the cell membrane and cannot complete its task of initiating cellular fusion.

TRI-001: Phase I/II safety, efficacy, and PK dose escalation trial

Seventeen HIV-1 infected volunteers (both treatment-naïve and -experienced) with CD4 counts ³ 100 and a viral load ³ 10,000 (4.0 log ₁₀) copies/ml were randomized to one of four doses: 3, 10, 30, and 100 mg of T-20 administered intravenously BID. Subjects discontinued any current antiretroviral medications 15 days before screening and remained off them through the course of the study. At Day 1, each subject was given a single dose at the assigned level and then monitored for safety and PK through a two-day washout period. Then therapy was restarted at the assigned dose and continued for 14 days.

No adverse events were reported. Pharmacokinetic assessment showed a strict dose-dependent response to T-20. The 100 mg BID dose maintained peak trough plasma levels of T-20 above 1 mg/ml² for a 24-hour period. HIV RNA viral load data³ also showed a dose-dependent response at 10, 30, and 100 mg BID. At day 18, all of those subjects receiving 100 mg BID had viral loads below the level of detection, with a mean suppression of viral load of 1.5 log₁₀. A similar dose-dependent response was observed on CD4 counts, which rose a mean of 52 cells in the 100 mg dose group. In conclusion, T-20 demonstrated potent antiretroviral activity in vivo and T-20 monotherapy was at least as effective as combination therapy in reducing viral load over 14 days⁴.

TRI-003: Phase II safety, efficacy, and PK trial

Seventy-eight HIV-infected individuals with a viral load of > 5,000 copies/ml (3.7 log₁₀) and either on no or a stable ARV regimen were randomized to one of six dose groups ranging from 12.5 to 200 mg/day. T-20 was administered either by continuous subcutaneous (SC) infusion or BID SC injection for 28 days. At entry, the mean viral load was 5.0 log₁₀ copies/ml with a mean CD4 count of 117 cells/mm³. Seventy-seven of the 78 had prior ARV experience (mean number of prior ARVs = 9) and 98% were PI-experienced (mean number of prior PIs = 3).

T-20 was well tolerated throughout the study period with only two subjects withdrawing due to adverse events. No difference in effect was observed between injection and infusion. The average maximum change from baseline in viral load was -0.3 to -1.6 log₁₀, with a greater magnitude and durability of response in subjects with baseline viral load of < 100,000 copies/ml (5.0 log₁₀)⁵.

About T-1249