T-1249 is a member of the new class of drugs called fusion inhibitors, so-called because they stop HIV from binding to and entering the human cell. Like T-20 (enfuvirtide, Fuzeon), T-1249 targets the HIV glycoprotein known as gp41 which HIV uses to bind onto CD4 T-cells.

Roche suspended development of T-1249 in January 2004 due to difficulties with the formulation. The company is now attempting to develop technology to extend the half-life of peptide fusion inhibitors. T-1249 and T-20 were both initially developed by Trimeris Pharmaceuticals and then contracted to Roche for commercial development.

Dosing

T-1249 is administered by subcutaneous (under the skin) injection. A dosing study reported that 200mg once daily produced the greatest reduction in viral load while the 150mg once daily dose produced the largest CD4 cell count increase (Gulick 2002). Pharmacokinetic measurements at day 7 support once daily dosing. The 200mg per day dose requires four injections.

Side-effects

The first safety study of T-1249 conducted in humans found two serious adverse events: hypersensitivity reaction, characterised by oral ulcers, rash and fever, and severe neutropenia, a low number of neutrophils (a type of white blood cell).

Forty percent of recipients developed injection site reactions but these were deemed to be mild. Dizziness, diarrhoea, headache and fever have also been reported by recipients. No dose-limiting toxicity was identified.

Effectiveness of T-1249

Phase I / II safety and dosing studies were completed before development of this medication was halted. Dose-dependent decreases in HIV viral load have been reported. In study T-1249-101, the average reduction from baseline ranged from 0.29 to 1.96 log₁₀, with the best results from a dose of 150 to 200mg daily (Gulick 2002).

Resistance

The antiviral activity of T-1249 is not be affected by resistance to the approved antiretrovirals, including T-20 (Miralles 2001, 2003; Sista 2001). Resistance to T-1249 is associated with changes in the two helical domains of gp41 (HR1 and HR2; Heil 2003).

Key research

Miralles (2003) reported preliminary results from an open-label salvage study in which people who were failing therapy with T-20 (defined as 2 viral load tests between 5000-500,000 copies/ml) were given 10 days of T-1249 (192mg/day) while continuing their background therapy. Results on 24 of 50 subjects showed an average viral load reduction of -1.12 log at day 10. 15 patients had a 1 log reduction and 19 patients had at least a 0.5 log decline. Those who had been on T-20 for less than 48 weeks had a better response than those who had been on T-20 for over 48 weeks. No side-effects were reported.

Gulick (2002) reported on a phase I/II dose ranging study of T-1249 in heavily treatment-experienced HIV-infected people. Participants had stopped antiretroviral therapy for two week prior to entering the dosing study. Dosing by subcutaneous injections ranged from 6.25mg/day to 200mg/day for 14 days. Median baseline HIV RNA was 5.31 log and the median CD4 was 64 cells/mm³. 113 of 115 patients completed dosing. Dose-dependent decreases in HIV RNA were observed. The median maximum change from baseline ranged from -0.29 (6.25mg/day) to -1.96 (200mg/day) log copies/mL, and the maximum CD4 cell increase was 70 cells/mm³ at a dose of 150mg once daily. Pharmacokinetic measurements at day 7 support once daily dosing. At the highest dose (200mg once daily) patients were required to undergo four subcutaneous injections, since T-1249 is currently delivered in multiples of 50mg. Injection site reactions were reported in 57% of patients, and became more frequent in patients who received doses above 50mg. Other reported adverse events were headache (14%), fever (14%), lymphadenopathy (10%), candidiasis (10%) and diarrhoea (9%). It is unclear if these effects are related to T-1249. One hypersensitivity reaction, one fever associated with an injection site reaction and one case of neutropenia were thought to be drug-related.

Eron enrolled 72 people in T-1249-101 - a 14 day dose-ranging, monotherapy pilot study. All were treatment experienced with viral load over 5,000 copies. Following a two week antiretroviral wash-out period, volunteers were randomised to one of six dosing arms: 6.25mg once or twice daily; 12.5 mg once or twice daily; or 25mg once or twice daily. Of 72 individuals enrolled, 63 received at least one dose, and 61 completed the 14 day study period. Mean viral load was in the range of 4.95-5.54 log, mean CD4 from 84-146 cells, and the prior number of antiretrovirals to which participants had been exposed was ten. Of 194 treated-related adverse events, just two were considered serious: one case of hypersensitivity and one neutropenia. Aside from these, common side-effects were injection site reactions (40%); headache (11%); dizziness (8%); fever (8%); and diarrhoea (6%). Viral load responses and average trough concentrations were dose dependent, though at the 6.25mg dose there was no measurable virological effect. At the other end of the spectrum, those who received the twice-daily high dose exhibited an average viral load fall of 1.3 logs between 10 and 14 days after treatment begun.

Lambert obtained HIV isolates from 74 people treated with T-20. The isolates were tested in vitro for sensitivity or resistance to T-1249 at baseline and after 28 days of T-20 treatment. The inhibitory capacity of T-1249 was similar against baseline isolates and isolates with genotypic and phenotypic resistance to T-20.

References

Eron J et al. A 14-day assessment of the safety, pharmacokinetics, and antiviral activity of T-1249, a peptide inhibitor of membrane fusion. Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 14, 2001.

Gulick R et al. Complete analysis of T-1249-101: safety, pharmacokinetics and antiviral activity of T-1249, a peptide inhibitor of HIV membrane fusion. 42^nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract H-1075, 2002.

Heil M et al. Analysis of patient-derived HIV-1 isolates suggests a novel mechanism for decreased sensitivity to inhibition by enfuvirtide and T-649. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 615, 2003.

Lambert DM et al. HIV-1 isolates from patients treated with T-20 are sensitive to the second generation fusion inhibitor T1249. Third International Workshop on HIV Drug Resistance and Treatment Strategies, San Diego, abstract 10, 1999.

Miralles GD et al. Baseline genotype and prior antiretroviral history do not affect virological response to T-1249. Antiviral Therapy 2001; 6(Supplement 1):4.

Miralles GD et al. T-1249 demonstrates potent antiviral activity over 10 day dosing in most patients who have failed a regimen containing enfuvirtide (ENF): planned interim analysis of T1249-102, a phase I/II study. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 14LB, 2003.

Sista P et al. The fusion inhibitors T-20 and T-1249 demonstrate potent in vitro antiviral activity against clade B HIV-1 isolates resistant to reverse transcriptase and protease inhibitors and non-B clades. Antiviral Therapy 2001; 6(Supplement 1):3.