The Bay Area Reporter - November 5, 1999
Bill Snow ACT UP/Golden Gate Writers Pool

T-20 was developed originally as a mirror image of part of gp41 on the virus envelope in hopes that it would stimulate an immune response as a vaccine, but it didn't work for that. Almost accidentally some was put in with HIV at Duke University laboratory where it was developed and surprisingly showed activity against the virus. Unfortunately it is a peptide, which is a string of amino acids too large to be taken as an oral drug without being broken up by the digestive system. All ingestable drugs (pills and liquids) are smaller molecules; larger molecules like these must be delivered intravenously (directly into a vein) or by injection into muscle or below the skin.

So, in its first trials of T-20, Trimeris, the company that was created to develop it, looked at a variety of delivery mechanisms: intravenous delivered periodically or by a wearable pump and injected beneath the skin (subcutaneously). Earlier this year it was reported that the subcutaneous method was as good or better than the others were, and more convenient with fewer complications, so the company is moving forward with that approach.

'Late-breaker' talk

Dr. Jay Lalezari at Quest Clinical Research in San Francisco is the principal investigator for the current study at about 10 sites, including his and another site in San Francisco, ViRx. He gave a very exciting "late-breaker" talk at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) that illustrated the potential power of this approach for individuals failing other therapies, titled "Sixteen Week Analysis of Heavily Pre-treated Patients Receiving T-20 as a Component of Multi-Drug Salvage Therapy."

This study was actually the rollover for individuals who had been in earlier, short-term T-20 monotherapy studies, the ones testing various delivery methods. Participants were allowed to take any individualized antiretrovirals based on their history and resistance pattern. In addition, they self-injected 50 mg of T-20 twice daily. Of 71 participants, 62 had reached the 16-week evaluation point at the time of the conference and nine had left the study, leaving 55 evaluable patients. All were protease inhibitor experienced and 93 percent had taken all three classes of drugs, with an average of 70 CD4 cells and viral load of almost 100,000 (4.9 log). All had resistance mutations to nucleosides and protease inhibitors, and 55 percent were documented to be resistant to all three approved classes of drugs.

With minimal side effects (4 percent possibly related to T-20, with mild-to-moderate injection site reaction in 66 percent but only three voluntary withdrawals) the following very impressive results were measured. About 60 percent of all treated individuals, and more than 50 percent of the triple resistance patients had more than a log reduction in viral load, more than 30 percent went down to less than 400 copies, and 10-20 percent became undetectable. This result is unprecedented with other existing therapies in heavily treated multiply resistant patients. Furthermore, that benefit was shown to be independent of baseline viral load or the number of other antivirals taken (up to 10).

In an interview, Lalezari made the following points. These study participants were the hardest-of-the-hard to treat. All were progressing in spite of their use of multiple antivirals. He has no doubt that this will be the next major advance in HIV treatment. The only complications will be the difficulty of producing this drug and people's willingness to inject it with some local reaction. This means that its primary use will almost certainly be in advanced drug-experienced patients and that the company will need time to figure out how to manufacture the drug in sufficient quantities.

No placebo -- yet

The current study compares multiple doses of T-20 (50, 75, or 100 mg) given with a fixed combination of newly approved backup drugs, from each other class: Abacavir (NRTI), Amprenavir/Norvir (PIs), and Sustiva (NNRTI). One difficulty enrolling the study has been the requirement for participants never to have taken any NNRTI (Sustiva, Nevirapine, or Delavradine) so that the drug can be tested with a second new class of drug. There is no placebo, but for comparison purposes one quarter of participants will only receive T-20 after eight weeks of backup therapy if they do not have an adequate antiviral response. Initially there was a viral load limit but that has recently been removed.

This is a good study for individuals who have not had a durable response from other therapies, as the next larger set of trials set to begin in the first quarter of next year may have to have a placebo arm. The company and investigators are adamant that there cannot be a compassionate use or expanded access program because of the production difficulties, and in fact that there are yield problems that have to be resolved before they can even make enough drug for the next FDA licensing studies. Information about the present studies, which will determine the optimal dose of T-20 and its longer term effects, are given in the action box below.

Meanwhile, Trimeris has accomplished some important scientific goals. They have proven that fusion drugs will work, and they are working on a second peptide for T-20 non-responders. A structural biology group at MIT recently identified another site for fusion inhibition and is making that information available on a non-exclusive licensing basis to any company that wants to try to design small molecules to make oral drugs. Though that is probably years down the road, it is how the protease inhibitors were developed. T-20 also proves that you can use a peptide for treatment of HIV, which has only been used for insulin to treat diabetes and calcitonin, a hormone for bone disorders. Trimeris has also been exceedingly fair and open in the design of their trials and their openness to activist input.

The company recently set up a 50/50 partnership with the multinational pharmaceutical, Roche, which has experience manufacturing peptides and financial resources to move this drug and this concept ahead rapidly. This approach looks like really good news for those survivors who have been infected long enough to have worn out their antiviral welcome and for a new way to slow the virus in its tracks.

ACTion UPdate

How to enroll for T-20 trial

To learn more about the currently enrolling Trimeris T-20 trial (#206), call Dr. Jay Lalezari at Quest Clinical Research, (415) 353-0800 or Debbie Hildebrandt at ViRx, (415) 353-5623. If you have never taken an NNRTI (Sustiva, Nevirapine, or Delavirdine) and you are not doing well on current medications this is an opportunity to consider something that may help you and move this promising research forward.
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Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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