What's Taking T-20 So Long?
T-20 is the first member of a new class of anti-HIV drugs called "fusion inhibitors" that are designed to block one stage of HIV's entry into target cells. Because T-20 halts HIV at a unique point in the virus's life cycle, it is expected to be active against viral strains with diminished susceptibility to all currently available antiretroviral drugs. This singular resistance profile is one reason why the drug's sponsors, Trimeris, Inc. and Hoffman-LaRoche, have guided the development of T-20 with an emphasis on use in so-called "salvage" therapy.
When HIV infects a new target cell, it first binds to receptors on the cell's surface where it undergoes a transformation of shape, revealing a viral attachment protein called gp41. The gp41 protein anchors a hook-like structure into the cell's membrane. Then the gp41 pulls the virus package into contact with the cell's surface where the lipid bilayers of the cell wall and the viral envelope fuse and become one. After fusion occurs, the enzymes and RNA of the virus are emptied into the cell where they begin to replicate new virus.
T-20 is a small protein that matches a portion of the gp41 mechanism thought to pull the virus into contact with a cell's surface. If sufficient amounts of T-20 are present in the environment when gp41 is attaching itself to the target cell, the drug molecule will pair with an exposed segment of gp41 and block the movement of the viral envelope towards the cell surface. This is called fusion inhibition. A sister compound, T-1249 works in a similar way but on a different segment of gp41.
Since 1996, T-20 has moved through the first few stages of human testing, demonstrating that it is safe enough to continue to use and that it has anti-HIV activity at attainable doses. Now larger Phase III trials have begun that are designed to show if the drug is an effective treatment for reducing viral load when combined with other, conventional, antiretroviral therapies.
However, parts of the research agenda for T-20, including a broad expanded access safety study and a government-sponsored trial that planned to include T-20 among several other experimental drugs for patients with highly drug-resistant viruses, have been scaled back or put on hold until a sufficient supply of T-20 becomes available from the manufacturer. With early data indicating that T-20 can safely contribute to viral suppression and a small amount of data suggesting synergistic activity between T-20 and other experimental entry inhibitors, the limited current capacity of the sponsor to manufacture the drug deserves attention.
The production of T-20 on a commercial scale is a formidable task. The sponsors are building a first-of-its-kind chemical manufacturing plant in Boulder, Colorado, dedicated to synthesizing commercial quantities of large peptide molecules such as T-20 and T-1249. The current supply of T-20 for experimental purposes has been produced in laboratories and more recently by contractors in small pilot plants where the techniques of large-scale production are being engineered.
Until viable production methods are established and the commercial facility goes online, the pilot plants can only produce about 100 kilograms of T-20 per year. This is enough of the drug to supply about 1200 patients annually. According to statements recently made to investment analysts, the sponsors are projecting that the first production batch will leave the Boulder plant early in 2002. Until then, supplies of T-20 will be tight.
The long-awaited expanded access program, slated to begin this summer, expects to only have enough T-20 to enroll 450 patients worldwide, with 168 in the U.S. This is disappointing, given the critical need many people have for a drug that attacks a new target in the HIV life cycle. It is not expected that the supply situation will improve much between now and when the new plant begins to produce.
The T-20 molecule itself bears little resemblance to those of current AIDS drugs. The sixteen HIV drugs on the market in the U.S. are all relatively small molecules that can be absorbed through the intestines. They are also relatively cheap and easy to manufacture, as we see from the recent availability of generic versions of antiretroviral drugs made by firms in India and Brazil. In contrast, T-20 is a huge molecule of a kind never before manufactured on a commercial scale. It is also too large to be orally absorbed and must be injected under the skin twice a day.
T-20 is a string of 36 amino acids called a peptide (a peptide is really a small protein), and there are 14 different amino acids that make up the chain of 36. Amino acids are commonly called "the building blocks" of proteins. Proteins from food are digested into amino acids, which are absorbed, distributed by the blood, then used by the body to repair itself and to build the various proteins and enzymes it needs to operate. Strings of amino acids like T-20 can't be taken orally because the proteolytic (protein chopping) enzymes in the gut will break them down. The sequence of 36 amino acids that makes up T-20 needs to stay intact for the drug to do its work. Injecting T-20 under the skin bypasses the digestive enzymes of the gut and puts the full-length molecule directly into the body.
In the laboratory, machines can make very small quantities of T-20 by adding one amino acid after another in sequence to create a chain. When the peptide chain is complete, the molecules are separated by weight, and partially or incorrectly formed peptides are filtered out. But this process doesn't translate well into large-scale production. To insure correct assembly of the chain and prevent unwanted reactions that can't be easily controlled in the industrial setting, the amino acid building blocks have to be processed in a way that "protects" them until the chain is finished being built.
This is where it gets complicated. The manufacturer purchases the protected amino acids from third-party specialty chemical makers. The unprecedented quantities of "building blocks" required for the production of T-20 initially exceeded the capacity and experience of these suppliers. So, not only has the pharmaceutical company had to dramatically scale-up its factory capacity, so have the vendors. To insure a redundant backup supply, the manufacturer has decided that at least two suppliers should be capable of providing each crucial component. The system depends on over 125 outside vendors to provide 45,000 kilograms of protected amino acids and other chemicals just to produce 1000 kilograms of T-20. There are over 100 separate steps to assembling a T-20 molecule. The novelty and complexity of this process explains why supplies of T-20 will be limited until the logistics of production are settled.
After the T-20 precursor is assembled, the protecting molecules have to be removed and the remaining product must be purified. Then the purified T-20 is freeze-dried (lyophilized), inspected, tested for sterility, labeled and packaged. It takes about 10 weeks to assemble a batch of T-20 and another 30 days to freeze-dry and package the drug.
The next milestone for the manufacturer will be to produce a registration batch of T-20 for submission to the FDA. The FDA will conduct stability testing to determine the shelf life of the drug and to see if it needs refrigeration to remain stable. When the registration batch is submitted, the manufacturing process is officially frozen and can't be changed without resubmitting product from the new process for stability testing. Currently the sponsor expects to submit drug samples for stability testing by the third quarter of 2001. After the "lockdown" of the manufacturing process, larger, "validation" batches will start to go into production. Monthly outputs of 100 to 200 kilograms are projected by early next year. People with AIDS in need of new treatment options will expect the limited expanded access program to "expand" considerably at that point.
Barring any breakdown in the complicated chain of chemical and equipment suppliers, increasing quantities of T-20 should become available each month up until the time of approval, when a capacity of 400 to 600 kilograms per month is projected. Results from the Phase III efficacy trials are expected to be reported at the 9th Annual Retrovirus Conference in 2002. If this target is met, application for approval could be submitted to the FDA during the following six months. Though it's impossible to predict how the drug will fare in its continuing clinical trials, two years from now to approval may not be unthinkable. By mid-2003 the company anticipates being able to treat 40,000 patients per year. The development of T-1249 is thought to be running about two years behind T-20.
Trimeris officials have pegged the expected profit margin of T-20 to be in line with that for protease inhibitors. The profit, of course, will be added to the cost of making T-20. The price when and if T-20 is approved? Don't ask.
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.