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T-1249 Development Suspended

December 2003

As the New Year began, Roche and Trimeris announced that they had decided to halt further development of their experimental entry inhibitor, T-1249. The drug was a follow-on to T-20 (enfuvirtide, Fuzeon), the first-of-its-kind fusion inhibitor that received FDA marketing approval in March of 2003. Since then, and despite high expectations, sales of T-20 have been disappointing due to its steep price and difficulty of administration. The $20,000-a-year drug must be injected under the skin two times a day. Some patients begin taking Fuzeon, then stop after a month or two due to fatigue with preparing and administering the drug. Yet many others adapt to the routine without difficulty and enjoy sustained results; there seems to be no argument about the ability of Fuzeon to suppress HIV for those willing to stick with it.

T-1249 was the subject of high expectations because it was said to only require one shot per day and because it retained activity against virus that had become resistant to T-20. Trimeris now says that T-1249 has problems with its formulation that make once daily dosing unlikely.

Another factor that may have contributed to the decision is the progress being shown by several orally available entry inhibitors now in early clinical trials. Both Schering and Bristol-Myers Squibb have drug candidates in this class that could reach the market before 2008.

Just three years ago, T-1249 was said to be only about two years behind T-20 in the development pipeline. As the push to approve T-20 heated up, this timeline was extended. Now, after six months of lackluster Fuzeon sales it appears that T-1249, at least in its current form, is finished.

Trimeris says it has decided to address the drug's administration handicap before moving on. One line of research will try to find ways to extend the life of T-1249 and other peptide-based entry inhibitors within the body, possibly by protecting the peptide with molecules that withstand metabolism, such as polyethylene glycol or albumen. The companies have also signaled their intention to develop new drugs in the class. News of the cancelled T-1249 program was coupled with an announcement of a research agreement to "discover, develop and commercialize the next generation of HIV fusion inhibitors."

The companies have pledged in a press release that the 40 or so patients currently receiving T-1249 in a clinical trial will be assured continued access to the drug. It is not yet clear, however, how long this supply will be guaranteed after the date when the cancelled trial was scheduled to end. Out of luck will be those patients who are currently taking T-20 and may be developing resistance; they can no longer look forward to T-1249 for salvage.

Both T-20 and T-1249 are chains of amino acids called peptides. The peptides are matched to complementary parts of the HIV protein responsible for pulling the virus into contact with a target cell. The viral protein, called gp41, is attached to another protein called gp120, which becomes embedded into the surface of its target. As gp41 folds back upon itself, the lipid membranes of the virus and cell are brought into proximity where they begin to mix. When enough of the two surfaces are in contact, a pore opens between the virus and the cell and widens until they become one, a process called fusion. Both T-20 and T-1249 jam gp41's folding mechanism, which effectively blocks fusion.

While T-20 and T-1249 bind to certain overlapping regions of gp41, T-1249 also binds to parts of the protein beyond the reach of T-20. It has been shown in clinical trials that HIV that has become resistant to T-20 will retain susceptibility to T-1249.

The approval of T-20 was one of the bright spots in HIV therapeutics last year. It was the first drug of a novel class and promised a respite to the growing number of people who have run out of treatment options among the conventional classes of drugs. Its discovery and development over the past 10 years has been an inspirational story of a small company pressing forward with a novel ideal against formidable obstacles. The news that further development of T-1249 has been curtailed is disappointing.

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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