American Foundation for AIDS Research, August 2002
Kristen Kresge

Introduction

Some of the most promising news from the 14th International AIDS Conference, held last month in Barcelona, Spain, included the results for the first of a new class of AIDS drugs called fusion inhibitors. This novel class holds hope for the growing population of treatment-experienced patients who have developed single- or multiple-drug resistance to the current market of antiretrovirals.

Currently available HIV drugs focus on preventing virus replication by targeting either the protease or reverse transcriptase enzymes. But fusion inhibitors hit the virus at an earlier stage. They are designed to prevent HIV from ever fusing with a host cell and inserting its genetic material.

The furthest along of any experimental drugs in this new class is T-20, a drug co-developed by Roche and Trimeris. (T-20 is also known as enfuvirtide or by the brand name Fuzeon.) Phase III data indicate that T-20 has considerable efficacy even for patients who have run through most standard drugs. But with questions growing about its usage and pricing, some doctors are reluctant to hail it as a "miracle drug" for resistant HIV.

The T-20 results come from two Phase III trials, known as TORO 1 and TORO 2. These included nearly 1,000 heavily treatment-experienced patients. Trial volunteers had been exposed to 11 or 12 previous antiretrovirals and started the study with HIV viral loads greater than 5,000 copies per milliliter. They were prescribed an individually optimized combination therapy of three to five standard anti-HIV drugs with or without T-20.

After 24 weeks in the TORO 1 trial, 20% of the volunteers taking T-20 had viral loads of less than 50 copies per milliliter. Only 7% in the control arm had equivalent reductions in viral loads.

The T-20 results in the TORO 2 study were a little weaker: at 24 weeks, 12% of patients receiving T-20 along with combination therapy had viral loads below 50 copies per milliliter, and 5% of those not receiving T-20 reached the same level.

"The results were very encouraging," said Dr. Jay Lalezari, lead investigator in the TORO 1 study and Director of Quest Clinical Research in San Francisco. "We've had enormous success at treating the later, more aggressive stages of HIV."

This 24-week data will be the basis for an application to the United States Food and Drug Administration and the European Union later this year. Roche and Trimeris have fast track approval status from the FDA, based on T-20's potential to help people who are unable to suppress their drug-resistant HIV with the current antiretroviral combinations, an area of treatment referred to as salvage therapy.

"Clinicians have a new card to play," said Dr. Keith Henry, director of HIV Clinical Research at Hennepin County Medical Center in Minneapolis, who sees T-20 as having a definite role in salvage treatment. But Henry cautioned that the TORO 1 and 2 study populations with highly drug-resistant HIV are not the ideal targets for adding a new class of drugs onto standard therapy, because this represents a "sub-optimal strategy for approaching HIV."

HIV does develop resistance to T-20. With only 24-week data available (follow-up will continue out to 48 weeks), Henry finds it hard to imagine years and years of use with T-20. "Durability would definitely be an issue if it's the only drug that's pulling the weight," he said.

In the clinic, Lalezari observed the most promising T-20 results in volunteers who had never taken the protease inhibitor Kaletra. They could then receive a regimen in which Kaletra and T-20 worked together to suppress HIV. Kaletra, manufactured by Abbott Laboratories, is a combination of the protease inhibitor lopinavir plus a small amount of ritonavir to achieve very high lopinavir levels in the body. These levels can overcome a certain amount of prior resistance to protease inhibitors on HIV's part. As with T-20, HIV can develop resistance to Kaletra if it is administered without active supporting drugs.

Lalezari's advice to practicing clinicians is to delay prescribing Kaletra until it can be used along with T-20 in salvage therapy. When administering the two together in this fashion, he saw major improvements in multi-drug resistant patients who were beginning to lose weight and get sick. "Our percentage of success was extraordinary," said Lalezari, referring to the number of patients whose viral levels fell below 50 copies per milliliter with T-20 and Kaletra. The use of T-20 alone in patients who had already failed on Kaletra was not as successful.

Henry believes that T-20's ideal role could be as a component of "induction/maintenance" therapy. This strategy would utilize T-20 as part of an optimized regimen of HIV drugs to get viral levels to an undetectable level (below 50 copies/mL). If this were achieved, after six to twelve months of receiving T-20, the drug could be withdrawn. The patient would receive the standard combination therapy alone, and T-20 could be reserved for occasions when HIV rebounded. This approach helps reserve available classes of HIV drugs for later use by preventing patients from burning through antiretrovirals, one by one as HIV develops resistance to each active drug in a succession of suboptimal regimens.

"We don't know about induction /maintenance regimens," commented Lalezari, but "it's an attractive idea."

T-20's Price

T-20's final role in salvage therapy may well depend on its price. Since the trial data were released in Barcelona, T-20's eventual market price has become a major concern. Roche has made no comment on pricing and will not do so until the drug is approved and available, said Heather Van Ness, the director of Product Public Relations at Roche Pharmaceuticals. Still, she acknowledged, "It will be more expensive than existing therapies."

This is due to T-20's structural complexity. Unlike most drug candidates, which are small molecules, T-20 is a synthetic peptide, or protein sequence made up of 36 connected amino acids. The synthesis of T-20 requires 106 steps. T-20's manufacture requires specially built equipment, and Roche is refurbishing a plant in Boulder, Colorado solely to produce T-20. Ness could not provide an estimate on the manufacturing costs of T-20.

"It's hard to imagine that there would be widespread use at the price being quoted," said Henry, referring to an early July Wall Street Journal article that reported estimates of the annual cost per patient being anywhere from $12,000 to $15,000 and above.

"All of the numbers that are floating around are analyst speculations," responded Roche's Ness. "We are investing $500 million dollars to develop fusion inhibitors."

The analysts' price forecasts could not come at a worse time for the AIDS Drug Assistance Programs (ADAPs). With most states' ADAPs in dire financial straits, the programs' ability to cover their low-income, uninsured clients' use of expensive new drugs is doubtful. In New York State, ADAP is taking a financial hit from an increase in enrollment, as well as from longer enrollment periods. That state's ADAP deficit is expected to reach $15 million this year, and New York is better off than many other states.

Use of T-20 will increase the overall cost of antiretroviral therapy, forcing ADAPs to begin prioritizing, or even cutting, their services. This might mean placing more restrictions on enrollment, or the state ADAPs might end up simply excluding T-20 from coverage because of its price tag. They would then direct patients to Roche's assistance program for indigent patients, but there is no guarantee that everyone in need would receive the drug.

Roche and Trimeris will begin enrollment in an expanded access program for T-20 on Sept. 1, although drug supply will not be available until the beginning of October. The modest program will provide T-20 to a maximum of 1,200 people worldwide – including only 600 in the United States. The program will be open only to those with a CD4 count of less than 100, a viral load of greater than 10,000 copies per milliliter, and the inability to construct a successful treatment regimen without T-20. The treating doctor will initiate the enrollment process and positions will be filled on a first-come, first-serve basis.

Administering T-20

The dosing requirements of T-20 also deserve consideration. The drug is injected twice daily under the skin. This method of administration is necessary to get the large, unstable molecule into the body. T-20, once inside the body, has minimal side effects partly because the drug directly enters the blood, acts and breaks down without ever entering cells.

But getting it into the body is the real problem. Before injection, T-20 must be taken out of refrigeration and combined with a sterile water solution in a syringe. The mixture must then sit at room temperature for 30 minutes to ensure proper mixing. This time-consuming procedure makes taking T-20 while working or traveling rather difficult.

"It's kind of inconvenient," said Matt Sharp, a treatment activist and writer who is taking T-20 in addition to standard anti-HIV therapy.

The problems don't stop with preparing T-20 for injection. Roche and Trimeris report that "most patients" receiving T-20 in both TORO studies experienced injection site reactions – nodules that appeared on the skin where the drug was injected. These nodules can remain for several weeks. In the TORO trials, only three percent of patients discontinued use due to these reactions.

Those taking T-20 have to inject the drug in a different place on the body every time they self-administer it. Since injections must be taken twice daily, "that doubles the issue," said Sharp. "Even if it were once a day it would be better."

Dr. Keith Henry urges clinicians who are considering T-20 for patients to "carefully look at patient populations," including their motivation to stick with the dosing regimen. "Injections are not the most user-friendly things to think about," says Henry.

Adherence to the complicated dosing regimen is likely to be less of an issue for those desperately needing T-20 for salvage therapy. "It would be really nice if there was another method of delivery," said Sharp, "but I'm glad it's there."

This article has been reprinted from the Treatment Directory at amfAR.org

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Copyright © 2002 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).

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