American Foundation for AIDS Research, April 2004
Elizabeth Paukstis

February 2004 — For people who have exhausted their treatment options and have even become resistant to the salvage drug T-20 (Fuzeon), a glimmer of hope still shone in phase II clinical trials. This was T-1249, an injectable peptide similar to T-20 that could suppress T-20-resistant virus. Like T-20, T-1249 prevented HIV from fusing with cells.

What distinguished T-1249 was its ability to defeat virus that had overcome the powers of T-20. Although a small study suggested that the longer a person was failing on T-20 the less effective T-1249 would be, the drug remained a possible recourse for people with few treatment options. T-1249 also had a longer half-life, allowing for a once-daily injection, instead of twice daily as with T-20.

But T-1249’s journey ground to a halt in January when Roche and Trimeris, the codevelopers of both compounds, announced that they were suspending the drug’s development. In conjunction with this, Trimeris laid off 30 employees who were working on T-1249.

Technical Difficulties
“There were technical problems related to the formulation,” stated David Reddy, HIV franchise leader for Roche. “One of the issues is that this molecule is different from Fuzeon. The type of technology used for Fuzeon doesn’t lend itself as easily to T-1249.”

Dani Bolognesi, chief executive officer of Trimeris, said a problem emerged when the company began making larger amounts of the drug. “In small batches, things worked fine. But as we began to scale up, we realized that we would have difficulties with a stable formulation.”

Yet when pressed for details of the problem, company officials were reluctant to offer any. “There were reports in the clinics of increased viscosity, which impacts the delivery of the drug,” Reddy said. “But if we get into manufacturing and other processes, then it becomes a legal issue. I don’t want to release sensitive information.”

Chris Barnett, a self-employed San Francisco resident who has been taking T-1249 for over a year, found the news bewildering.

“What we want is a drug that is both effective and patient friendly.”
– Dani Bolognesi

Barnett is one of 40 people enrolled in T1249-105, the phase II trial testing T-1249. “I was very surprised to hear about it,” commented Barnett. “For me, it’s been an incredible drug. I don’t know if I’m an anomaly, but T-1249 has produced remarkable results for me.”

Barnett switched to T-1249 when T-20 stopped working for him. Since then, his viral load has dropped and his energy is back. “I found out that I was positive 15 years ago,” Barnett said. “In 1995, I was really sick. Now here it is nine years later, and I’m doing really well. I think T-1249 has a lot to do with that. For one thing, I have really been enjoying food again. For an HIV-positive person, dealing with all the meds, this can be an amazing thing. It has been really nice having an appetite again.”

Tom*, an Oakland resident also enrolled in the trial, echoed these sentiments. In the fall of 2002, after T-20 failed him and tests revealed that he was “basically resistant to everything,” Tom began taking T-1249. “I started out with 12 T cells and went to 100. The drug has really kept me going,” he remarked.

Roche and Trimeris representatives pledged that the 40 trial participants would continue receiving the drug for the full 96 weeks and beyond, if necessary. “The physician will make that decision,” Bolognesi asserted. “After the 96-week end point, we’ll be amending the protocol on a case-by-case basis.”

But the companies reject the idea of a “compassionate use” program, which could provide access to T-1249 for T-20-resistant people not enrolled in the trial. “There’s enough drug for people currently on the drug. The remaining supply of T-1249 will be used to support new research,” Reddy said.

Producing the Perfect Peptide
Although Roche and Trimeris deny that T-1249 was shelved due to probable low sales, they vow to introduce a more convenient candidate. “If we make a drug, we want [people] to use it,” declared Bolognesi. “The importance of convenience means moving from twice-a-day administration to once a week. The [T-1249] molecule is not gone, but what we want is a drug that is both effective and patient friendly.”

To achieve this goal, the companies propose extending the half-life of the new peptide. Regarding the form of the new drug, Bolognesi conceded that they have a variety of options. “All of our new peptides are candidates for the half-life extension. It is not inconceivable that we might want to apply the half-life technologies to T-20 itself.”

When a new drug will enter human testing, let alone be available to the general public, is unclear. Bolognesi stated that they will introduce a candidate in 2004 and begin preclinical development. “We’re very close to identifying what it is we want in a peptide. The challenge is to build convenience into that peptide. That part’s not ready for prime time.”

Reddy was more cautious. “These developments don’t occur overnight,” he said. “We’re talking a number of years here.”

Roy Gulick of Cornell University in New York offered a more optimistic perspective. “Aside from fusion inhibitors, there are many entry inhibitors in development,” he remarked. “While we’re not 100% sure, there is every reason to think that people who responded to T-20 should respond to these other entry inhibitors.”

Meanwhile, patients who develop T-20 resistance now face a more daunting future — what was relatively close at hand with T-1249 is now much further away. And those who need T-20 may hesitate to take it without the prospect of a drug that overcomes T-20-resistant virus. As Tom put it, “It’s terribly disappointing. This probably throws back development of another fusion inhibitor for years.”

*This is an alias.

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