Long Path to Approval
A Look Back at the Road to Fuzeon
On March 13, 2003, the U.S. Food and Drug Administration granted Trimeris, Inc. approval to sell T-20, brand name Fuzeon, generic name enfuvirtide, the first of a new class of HIV drugs called fusion inhibitors.
GMHC Treatment Issues has been tracking the development of T-20 since 1996. Here's a look back at the path from laboratory to pharmacy via some edited excerpts of reports that have appeared in these pages. It's interesting to note how the core issues that challenge us today with this drug were identified early on: it's potential for salvage therapy, the problematic need for injection, its difficulty of manufacture, and consistently, the expected high price of T-20.
September 1996Theo Smart -- New Wave Antiretrovirals
Despite enthusiasm at the Eleventh International Conference on AIDS in Vancouver over recent advances in anti-HIV therapy, it will be a long time until there are manageable combinations of easy-to-tolerate drugs that work for everyone. New agents are needed particularly for the many individuals who already have failed on protease inhibitors.
There were a number of presentations on T-20, a compound made by Trimeris, Inc. "T-20 is the most potent agent that we've ever looked at [in a mouse model for HIV infection]," according to Paul Black of the FDA. Since the drug is a protein, there is a fear that it could provoke an antibody response that may inactivate it. Another potential problem is that the compound cannot be taken orally since it is broken down by acids and enzymes in the digestive tract. In its current form, the drug would have to be given as an injection two or three times a day. Trimeris is considering administering the drug via "mini-osmotic pumps," small implanted devices that secrete a constant level of drug over time. First, though, Trimeris intends to determine whether the current form of T-20 has activity in people. Dose-ranging studies are planned to begin by the end of the year.
December 1997Dave Gilden -- Medical Merry-Go-Round
T-20 is one of the few novel (as opposed to merely "new") drugs exhibiting efficacy in early human trials. Four volunteers receiving 100 mg every 12 hours for 14 days experienced a -1.5 log drop in their viral loads. All achieved unquantifiable viral loads (less than 500 copies). Since this dose-finding trial only lasted two weeks, it is impossible to tell what T-20's ultimate effects are, but clearly the principle works.
April 1998Dave Gilden -- Expect No Miracles
A portable pump ensures a constant level of T-20 in the body. Although it is a very small removable device that delivers drug through a thin tube inserted just under the skin, many persons with HIV question its practicality. Also, a new pump needs to be purchased every five years for about $4,500, and supplies add another $1,000 per year. This expense would be on top of the anticipated high cost of T-20 itself. The drug presents a manufacturing challenge due to its lengthy, specific amino acid sequence. However, T-20's non-oral administration plus the lack of kidney or liver involvement in its metabolism means that it avoids many of the major toxicities of current antiviral drugs.
An article published in the Journal of Virology described the ease with which HIV in cell cultures can develop resistance to T-20. Resistance remains to be documented in the human body, but the cell culture results are comparable to what has been seen with protease inhibitor resistance.
Trimeris is concentrating on developing T-20 as salvage therapy, where lack of treatment options would make its shortcomings acceptable. Trimeris' two upcoming trials will test T-20 in 72 people who have failed to have a stable response to indinavir, ritonavir or nelfinavir.
January 1999Dave Gilden -- Three New Drugs
The results of Trimeris' salvage protocol, TRI-003, were reported at a late-breaker session concluding the 6th Retrovirus Conference. At week 2, viral load drops in this heavily treatment-experienced population averaged -0.3 logs to -1.6 logs, depending on dose. The negative part is that by week four, viral loads in all the trial arms had returned to within 60 percent of baseline. A genetic analysis performed in a preliminary T-20 clinical trial found resistance mutations previously identified in cell culture studies.
Nonetheless, one should not dismiss T-20's accomplishments. The recent trial tested the compound in the population that is hardest of all to treat. Another positive outcome of this trial was that the simpler mode of administering T-20 via twice-daily subcutaneous injections appeared as effective as a portable infusion pump. So far, the major side effect has been rash and bumps at the injection site.
The principal stumbling block at present is synthesizing this 36-amino acid molecule at reasonable cost. Trimeris claims to be slowly expanding production and attaining economies of scale, but the compound will always cost substantially more than any of the anti-HIV agents now in pharmacies.
September 1999Gil Shepard & Theo Smart -- New Drug Harvest
T-20, the first fusion inhibitor, is now being developed by Trimeris in partnership with Hoffmann-La Roche. To the credit of Trimeris, the company has made salvage therapy the focus of the drug's development; but T-20 is costly to make and until the recent collaboration with Roche, resources for the young company have been limited. Still, Trimeris has been able to mount a few studies.
Results from the most recent of these were presented during a late-breaker session at ICAAC. Subjects took 50 mg of T-20 twice a day (bid) in addition to an individualized oral regimen chosen on the basis of each patient's history and genotypic results. At week 16, in an as-treated analysis, 36 percent (20 of 55) were below 400 copies and 20 percent were below 50 copies. But are these responses sufficient?
In the earlier dose-ranging studies of T-20, there was a clear dose-response to the drug, which peaked at the highest dose tested, 100 mg bid -- twice the dose currently under evaluation. Why did Trimeris not proceed with the 100 mg bid dosage? [Note: Fuzeon was approved at a dose of 90 mg twice daily.]
For one, this is a costly agent to synthesize and will likely be quite expensive when it is marketed. Aside from the issue of cost, there is a limit to how many injections a person can tolerate. But is there a danger that the doses being used are suboptimal? Even 100 mg bid may be inadequate. Yet, there is no way of telling since that was the highest dose ever tested. And if it is the cost of therapy that is the dose-limiting factor, how much is cost-prohibitive? Is $15,000 a year too expensive? $30,000? Just how expensive are we talking? At present, neither company is anxious to say.
April 2001Bob Huff -- What's Taking T-20 So Long?
In the laboratory, bench-top machines can make very small quantities of T-20 by adding one amino acid after another in sequence to create a chain. 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 1,000 kilograms of T-20.
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, inspected, tested for sterility, labeled and packaged. It takes about ten 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.
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. 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.
July 2001Bob Huff -- What Does R&D Really Cost?
Trimeris, Inc. was founded in 1993 as a development-phase company involved with the discovery and development of peptide-based fusion inhibitors. Trimeris has a royalty-free patent from Duke University for the underlying concept of fusion inhibition with peptides. From inception to March 2001, Trimeris has spent about $130 million on administration and R&D (research and development). The company has never made a profit and does not anticipate any sales until early 2003.
In July 1999, Trimeris announced an agreement with Roche to develop and market T-20 worldwide. Since then Roche and Trimeris have shared U.S. development expenses for T-20 equally. Under the agreement the two companies will split revenues on sales within the U.S. and Canada. In the rest of the world, Roche will bear all development costs and pay Trimeris royalties on sales. The agreement with Roche was made at a point when Trimeris had invested approximately $45 million in research. After the Roche agreement was signed, R&D expenses increased rapidly as expensive Phase III trials were begun. By the end of March 2001, cumulative R&D expenses had reached $170 million.
During the first three months of 2001, Trimeris reported spending almost $14 million on R&D. Since Roche matches this amount, total R&D for the quarter ran $28 million. At this rate, with no increases, over $360 million will have been invested in T-20 by the end of 2002. Expenses for international trials are Roche's exclusively, which introduces some uncertainty in predicting the ultimate investment required to launch T-20.
If opportunity cost, calculated at a rate of 10 percent compounded quarterly is considered, the investment figure could rise to $460 million. That said, Trimeris has told investors to expect worldwide sales of T-20 to reach $500 million per year.
March 2002Bob Huff -- Drugs in Development
The outlook for entry inhibitors is looking better. T-20 from Trimeris/Roche is likely to be the first of this new class of drugs to be approved, although that may be up to a year from now. Apparently the generic name for T-20 has been settled; initially known as pentafuside, T-20 will now be called enfuvirtide.
March 2002Fred Gormley -- T-20 Diary
Dear Diary, Today my doctor informed me that my first dose of T-20 is just a week away! How I have yearned for this day! Scalding tears of joy spilled copiously down my face onto my heaving, bountiful pectorals, drenching my Donna Karan cashmere sweater. The precious fusion inhibitor would soon be mine. ...
Well, of course not. One doesn't live in New York, wear all black, and reach the age of 50 (14 years aware of my positive HIV-status) to get exuberant about anything. What really happened was that, after waiting since early December, my shipment was finally coming in. As the result of a new safety study, I was the first of three people in Howard Grossman's office to get T-20. It wasn't easy, but the effort wasn't mine. The pharmaceutical companies (Trimeris and Roche) set up a specific time when physicians around the country had to phone in; availability was on a first-come, first-served basis, and there was limited drug to be had. The volume of calls overwhelmed the insufficient phone lines, and getting through was hairy. Several weeks later, I found out I had made it, and that the meds would come my way.
The instructional video! It answered all my innermost, private questions! I ran to my Sony Wega and hugged its big flat screen.
There was nothing new here for me (except for the reconstitution process -- T-20 is a protein, and its powdered form must be mixed with sterile water to be administered), so I concentrated on the tape's production values. Professionally done. High-quality video. San Francisco locale. And there's skin! The demonstration subject doffs his shirt to give himself a shot in his well-tended abs.
At the doctor's office, I did my first hit under Liza's direction. No problems, but one potential annoyance, a possible future deal-breaker. The reconstitution takes 15 to 20 minutes if you tap the bottom of the vial and gently roll it around (no shaking!) and somewhat longer if you just let it sit. For someone like myself who greets the day with pills at 8:00 (no food!), pills at 9:00 (food!), protein shake, two packets of testosterone gel drying on my belly as well as the usual get-ready-to-go-out-the-door routine, another extended multi-step procedure (repeated at night) could quickly lose its charm and novelty. I'll bear with it, though.
So, I've just given myself my fifth poke with no adverse reactions evident so far. Some people have complained about swelling under the skin at the injection site, but anything I've ever shot subcutaneously has given that effect; mine goes away within an hour. There was some itching with the in-office dose, and a vague feeling of momentary heartburn, which may have been coincidental. It'll go as it goes. It'll work or it won't, or the results will be ambiguous, as most drugs are when you're on a heavy regimen. We'll see. ...
April 2002Lei Chou and Anne Donnelly -- ADAP Strapped
Pressure on state ADAPs (AIDS Drug Assistance Programs) is expected to increase as new drugs such as T-20 become available next year. Access to these newer products will probably require prior authorization. Additional pressure will likely come from rising unemployment and loss of insurance; a steady level of new HIV infections and a possible rise in AIDS cases; the emergence of long-term drug side-effects; and the tightening of state Medicaid programs.
July 2002Bob Huff -- T-20 Expanded Access Limps Forward
In a conference call with community members, Roche revealed their plans for wider release of T-20 through an expanded access program. Current plans (and there have been so many it wearies me to type this) call for greater drug availability on October 1 when the company expects about 600 slots to open up in the U.S. Although the hoops that doctors must shimmy through have been minimized, a hitch may come when providers learn they have to complete a full day's training on proper T-20 administration technique. Because T-20 is a fragile peptide that must be carefully reconstituted with sterile water before using (swirled not shaken!!), this training isn't a bad idea. Access won't be worth a hoot if patients fail to benefit from the drug because they never learned how to prepare and inject it properly.
October 2002Bob Huff -- Onward T-20
The FDA announced they have given T-20 priority review status for approval, which means they must say yea-or-nay by March 16, 2003. T-20 sponsor Roche is happy about this, but a persisting problem with drug production has them downplaying expectations about actually being able to deliver the drug to everyone who'll need it. Roche has scheduled a meeting with community members next month to discuss this issue, its expanded access program, and rumors of "golf-ball-sized nodules" at the site of injection.
December 2002Bob Huff -- Five New Drugs
Fuzeon (T-20) is the Godot of HIV therapy. The long awaited, much delayed, first agent of a completely new method of suppressing HIV infection is definitely at the top of the FDA's to-do list for the New Year.
But a green light from the FDA won't be the end of the wait for some. Because of manufacturing difficulties, Hoffmann-La Roche (Roche), the drug's sponsor, has announced that availability of Fuzeon will be limited during the first year following approval. Allocating the drug fairly may be a challenge since there seems to be a gap between those in greatest need and those who might expect the greatest benefit from the drug. People who add Fuzeon to a suite of other drugs active against their virus are likely to have a much better response than those who take it on top of their worn-out regimens. The catch here is that people with other options may not want to go through the unpleasantries of twice-daily injection, while those with no other options may not find Fuzeon the life preserver they need.
January 2003Lei Chou -- Boulder Blues
On Valentine's Day, Roche invited state ADAP directors and community activists to a meeting about T-20 pricing at its manufacturing plant in Boulder, Colorado. Dani Bolognesi, the chairman of Trimeris, kicked off the meeting with "The Fuzeon Story," the history of the drug from discovery through development. Their excitement about the pending FDA approval was palpable. They say they are also continuing the development of pharmaceutical peptides by looking at pegylation, pushing towards eventual once-a-week dosing.
It was revealed half way through his presentation that the price has already been decided upon: "No, of course I can't tell you what it is!" Roche's David Reddy said. At this point in the meeting they assured us that pricing discussions will continue and then herded us out of the meeting room and onto a tour of the plant (in hard hat and goggles). They showed us giant tanks that hold the raw materials and solvents used in production, different machines that do the assembly of amino acids, and a myriad of dryers and washers. The place smelled like a gas station, with water leaking from ceilings, and a little room with two computers and two workers overseeing the entire process.
After lunch, each ADAP director told those remaining about the crisis facing their programs. Fuzeon will only come to those who need it at a cost of reduced formularies and stricter financial eligibility criteria. With a scary new Medicaid proposal coming out of the White House, most states will wait until the dust settles before committing to major initiatives. The price of Fuzeon will be the first test of this new reality we live in. One hopes that Roche will do the right thing. They've certainly been informed.
January 2003Bob Huff -- Informed Access
Community representatives met with T-20 makers Roche and Trimeris in New York in January to get a briefing on plans to distribute the injectable fusion inhibitor as soon as it is approved. Roche will contract with a third-party pharmacy service corporation to deliver drug kits (either by mail or to selected pharmacies), staff a patient assistance hotline and handle prescriptions for patients unable to pay.
The patient support component of this system will be critical if patients are to have good outcomes when using T-20. It's becoming increasingly clear that T-20 is not an easy drug to take and the decision to begin enfuvirtide therapy should be made in consultation with a physician who has been trained in the correct preparation and administration techniques. Resistance to T-20 can develop fairly quickly if full doses are not taken on a consistent basis, so an individual's informed commitment to making the regimen work is a must.
Although no price has been announced for Fuzeon, it is expected to be a doozy. People with private insurance will be covered, as eventually will Medicaid beneficiaries (hopefully). But this leaves a large gap in the middle, especially if state ADAP programs decide they cannot afford to add this budget buster to their formularies. Roche has promised to make Fuzeon available to any who cannot afford it through a patient assistance program administered by the third-party distributor. Details of their plan to patch over access problems remain to be seen.
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.