For 65 of the best-connected aids docs in America, Wednesday, December 4, 2001, was do-or-die time. Scurrying to their phones, they might have been teens trying to score Strokes tickets from a radio giveaway. But, in fact, they were dialing to save lives. Swiss drug giant Roche was offering early access to its hot new treatment, Fuzeon (still dubbed T-20 at the time) to "salvage" patients, hard-luck cases who had burned through every treatment option and come to the end of the line. They had 70 CD4 cells, or 37, or two. And there were several thousand such desperados in the U.S. alone. But part of their hard luck was that Roche, which had partnered with Fuzeon's original developer, small-fry biotech Trimeris, claimed to have enough drug for only 168 HIVers in the U.S. (450 worldwide). The slots would be filled on a first-call, first-served hotline. If your doctor's name wasn't on the list of 65, you weren't, either.
Longtime HIV specialist Howard Grossman's name was on the list. And at 3 p.m. EST he was on the phone -- his cell in one hand and land line in the other -- speed-dialing the early-access number for Fuzeon (generic name: enfuvirtide). Even the receptionists and lab techs were in on the action, sitting two to a chair in his New York City offices, falling over each other to grab incoming calls. The phone-bank burlesque was worthy of Jerry Lewis.
Grossman's multi-pronged attack paid off. After a mere six minutes of busy signals, he managed to connect and to reserve the drug for three patients, the maximum that Roche permitted any single physician. When one of Grossman's cross-town colleagues got through to the hotline at 3:13 p.m., all 168 hopes were already gone.
To be sure, a 450-patient "open label exploration" was a far cry from the 3,000-strong expanded-access program that treatment advocates had clamored for (see "Do Activists Play Favorites?"). Roche insisted that the 70-something-step production process was to blame for the crimp in the Fuzeon spigot. It was, of course, not the first time a drug company had balked at giving free meds to sick HIVers.
What is a first is the drug itself: Fuzeon is the first (though clearly not the best) of a new kind of HIV meds. Called fusion inhibitors (FIs) -- they inhibit HIV from fusing with a healthy CD4 cell -- these drugs are actually a subset of the futuristic drug class known as entry inhibitors, all of which work their magic against HIV before the virus can infect the body's immune cells. The beauty of this radical new approach isn't simply that it offers a fourth strategy to augment a HAART combo. By disabling HIV outside the cell, Fuzeon and its cousins are likely to avoid the terrible tidal wave of side effects caused by drugs that have to mess with and muck up a CD4 cell's machinery because the HIV is already inside. At the big Retrovirus confab last February, one enthusiastic researcher, the University of Texas' William O'Brien, MD, heralded the "decade of the entry inhibitors," with fusion inhibitors the first wave.
It's easy to sympathize with the communal fervor of industry, researchers and HIVers themselves. Never mind that this first-at-bat "FI" requires refrigeration, complex prepping and twice-daily injections. Or that it causes injection-site inflammation. Or that, if the rumors of its $15,000 annual price tag are true, it will be the priciest HIV med ever. Or even that data from the most recent trials paint a picture of a middling beneficial work-in-progress rather than the next great HIV lifesaver. Because with nothing else on the immediate treatment horizon, Fuzeon is the only game in town. (See POZ, "This Little Drug Went to Market," May 2000, and "Birth of a Notion," June 2001.)
SALVAGE IS A DIRTY BUSINESS
Fred Gormley was one of Grossman's lottery luckies. HIV positive for more than a decade, this longtime production manager of GMHC's Treatment Issues newsletter had tried every nuke, non-nuke and protease inhibitor -- at least twice. Waiting for Trimeris to overnight the Fuzeon -- it took three months -- Gormley survived a case of drug-resistant candidiasis (thrush) and a bout of wasting. Still, the AIDS vet never lost his sense of the absurdity of AIDS. In his diary entry for March 1, 2002, he celebrated the drug's imminent arrival, tongue firmly in cheek: "My doctor informed me that my first dose of Fuzeon is just a week away! Scalding tears of joy spilled copiously down my face. I exulted, whirled around his office, gleefully tossing several other patients' files in the air. The precious fusion inhibitor would soon be mine."
Grossman patient John Lesnick lucked out and got the drug much faster. With a 250,000 viral load and 20
CD4s, he was more than ready to jump-start his foundering quadruple combo. So, too, was Kat Perera, 37, a
Vermont mother of two and restaurateur. Although her numbers were much better than Lesnick's -- 240 CD4
cells, a 16,000 viral load -- she had just been tested as "resistant to most every drug" when her doctor
slipped her into the tail end of a small Fuzeon trial in early 2002. "Right away," says Perera, her viral
load dropped to around 3,000 and her CD4s climbed to about 360. For someone who once "could barely walk down
a driveway," life was looking brighter.
John Lesnick injects Fuzeon into his upper arm for lack of available plump places. But this "natural resister" is impervious to Fuzeon's charms.
1. Swab top of water bottle with alcohol and draw sterile water into syringe.
2. Inject sterile water into bottle (ampule) of Fuzeon, swabbing that with alcohol first, too.
3. Wait 20 to 40 minutes for clumps to dissipate and bubbles and fizz to disappear.
4. With a new syringe, suck up the mixture (wiping with alcohol swab first, of course).
5. Find soft, pliable skin into which to inject the Fuzeon. First: Wipe skin with what? An alcohol swab.
And Fuzeon can fairly be called a lifesaver for Rob Phelps. The 38-year-old freelance writer in Provincetown, Massachusetts, had struck out with virtually every single HIV med since his 1989 diagnosis. The protease "miracle" passed him by. In early 1999, he enrolled in a tiny Fuzeon trial as a last resort: Battling PCP, CMV and wasting, the once-strapping, striking Phelps weighed in at 119 pounds, with 13 CD4s and a viral load over a million. Two months after adding Fuzeon to his combo of four nukes and hydroxyurea (unconventional, but it works), his CD4s had soared to 500 and his virus had plummeted to undetectable. "It was a revolutionary breakthrough for me," Phelps says flatly. "HIV was killing me. Fuzeon made it a chronic disease."
WAS THE RUNNING OF THE BULL, BULL?
Fast forward to last July's 14th international AIDS conference in Barcelona, where, on day one, the results of a study (dubbed TORO for "T-20 vs. Optimized Regimen Only") were displayed -- to predictably heady headlines. Even the New York Times' temperamentally dour Larry Altman caught Fuzeon fever, and the paper's July 8 front-page dispatch from the confab led with the headline "Fusion Inhibitor Offers AIDS Lifeline." But as anyone who recalls the "eradication" hype at the 1996 conference can guess, the actual data, while encouraging, told a different story. According to TORO, which had 995 multidrug-resistant patients with an average of 100 CD4s and viral loads of 100,000 but lasted a measly six months, adding the fusion inhibitor to a triple or quadruple HAART regimen was beneficial: 30 percent on Fuzeon saw their virus fall below 400 copies, while only 15 percent of those on Fuzeon-free combos did. Similarly, the Fuzeon folks also boasted a five-to-10-fold viral-load drop -- meaning that a 100,000 count dropped anywhere from 500 to 1,000 -- not exactly to "undetectable." Still, at a press conference, company officials were happy to be quoted that the TORO results exceeded even their most optimistic expectations. But on the evidence, this was bluster. And ironically, the best news went largely unreported, because Roche/Trimeris was skirting the "injection" issue: While 95 percent of Fuzeon-takers reported injection-site reactions, only half characterized the pain as bothersome, and, better, only 3 to 5 percent dropped out due to it.
With no other big treatment advances at Barcelona, the timely TORO data filled the necessary news slot as AIDS-science success story. And in terms of hype, it was the grand-scale fulfillment of its earliest promise: a tiny, blink-and-you-miss-it 1997 study at the University of Alabama in which four out of four HIVers taking Fuzeon saw their viral load drop to below 500 copies in 14 days. Such results prompted the study's leader, AIDS heavy Michael Saag, MD, to gush that Fuzeon looked "as promising as protease inhibitors at a similar stage of development."
Sagg's protease comparison was apt, but mostly in unintended ways. After all, that new class of HIV meds was heralded as a treatment revolution in 1996, and it took several years for the drugs' legendary and legion side effects, resistance and other complications to correct the best-face first impression. Similarly, lost in Barcelona's media frenzy was the fact that the TORO study could reasonably be criticized as designed to get the best results possible. First, TORO looked at data only up to six months, leaving Fuzeon's long-term effectiveness, let alone its side effects and resistance profile, an open question. More significant, with an average CD4 count of 100 and viral load of 100,000, the patients in TORO could soundly be categorized as "moderate," unlike "deep" salvage cases like Fred Gormley and Robert Phelps, who were staring down the barrel of a gun.
This difference -- whether you're "moderate" or "deep" -- goes a long way to clarifying all the Fuzeon confusion. The healthier you are and, especially, the less drug resistance you have, the better this "salvage" therapy will work. According to resistance guru Daniel Kuritzkes, MD, of the University of Colorado, resistance to Fuzeon happens relatively quickly -- after just two viral mutations -- when other drugs in an HIVer's combo are not carrying their weight. TORO teamed Fuzeon with new-kid-on-the-block meds, such as newish nuke Viread [tenofovir] and the power-PI Kaletra [lopinavir/ritonavir], to which its 995 subjects hadn't already become resistant. In other words, the happy data may have been due to these drugs rather than Fuzeon. An earlier (and, at 48 weeks, twice as long) Fuzeon study in 71 truly "deep salvage" desperados who had far fewer drug options saw 30 subjects drop out because of drug failure, injection problems (at the time, the drug had to be infused with a nasty catheter) or both. Skeptics would say that to measure the true value of Fuzeon, one would have to factor in these grimmer data. After all, when Fuzeon hits the market next spring, unlucky HIVers who have already burned through Kaletra, say, and Viread may have no new meds to beef up the fusion inhibitor's brawn. Will it be a true shot in the arm or a pointless pain in the ass for these deep-salvagers?
WHO'S CALLING THE SHOTS?
The other radically new aspect of the drug is what the pros call its "mode of delivery." The fusion inhibitors appear to be too delicate to withstand the stomach's rough treatment, so marketing the chemical as a pill was impossible. Roche is understandably queasy about promoting Fuzeon's twice-daily injection requirement. And Grossman says, "The expanded-access program has given me a better insight on how difficult Fuzeon will be for many patients -- especially the time and care it takes to mix it." Still, pricks and prepping notwithstanding, HIVers are famous for putting up with a lot to stay healthy.
Roche is distributing an instructional video narrated by a chipper host, which Lesnick found amusing. Not so funny was the self-injection process with its time-consuming five-step prepping and, of course, the ouch! (See "Straight Shooting" and "Sticks of the Trade"). A freeze-dried powder, Fuzeon arrives in a little glass ampule. To get it into an injectable liquid state, it must be reconstituted by mixing with water in a syringe. Users are cautioned not to rush the 20-minute process (Perera says 40) -- only when the potion's pop-pop, fizz-fizz is finished is it ready to be drawn up and ever so slowly injected under the skin. At 12-hour intervals.
For Lesnick, Phelps and Perera, all this sifting and stirring became second nature -- an inconvenient but acceptable trade-off for the healing tonic. Phelps compares the ritual to a diabetic taking insulin. But he admits that his adherence leaves room for improvement. "Sometimes I'm out running around, and I come home late," he says. "But I can always blame it on my boyfriend." Phelps can afford to laugh: After six months on Fuzeon, he was able to go off his ball-and-chain anti-CMV Foscarnet drips. Today, his CD4s hover between 500 and 600, his viral load remains undetectable and his weight, looks and future are back. Still, this salvage success knows the score. "It's still scary," he says of the risks of resistance and his iffy combo. "You never know what's going to happen. But for these three years plus, it's been great."
Lesnick is a less happy camper. Another, unexpected complication dampened his enthusiasm: what Roche delicately refers to as the "injection-site reaction." You see, for a couple of days after each shot (particularly in the abdomen), the area of the injection often becomes red, sore and tender. A yoga devotee, Lesnick had a reaction so bad that rolling over in class was excruciating. He couldn't sleep on his stomach or side. The soreness was temporary but left a hard bump of scar tissue ("small subcutaneous nodules" in medicalese). Fuzeon must be injected into fatty folds of tender, supple skin, too -- hardened scar tissue from previous jabs simply won't do. After four months of twice-daily dosing, Lesnick was running out of places to inject. Perera, on the other hand, laughs ruefully that a lipo-related excess of belly fat has left her with plenty of soft flesh for shooting.
Still, Lesnick and Perera soldiered on. After all, they reasoned, Fuzeon was was worth all the bumps and bruises if it worked, right?
Except that, well, it didn't. Perera says that the initial dramatic improvement in her CD4 and viral-load counts after starting Fuzeon was "short-lived." Six months into the treatment -- just as she was enjoying the freedom from side-effects like diarrhea and nausea that had plagued her before her combo was tweaked to get the most out of Fuzeon -- her CD4s had fallen back to the mid-200s, and her viral-load had reset itself about 10,000 copies higher than before.
Self-injecting can be intimidating, but with practice, most Fuzeoners get used to the twice-daily sticks. Here, John Lesnick, Rob Phelps and Kat Perera share these 10, er, tips:
1. Take a shower to ensure that your skin is soft as can be before administering the shot.
2. Small-gauged needles such as those used for insulin are easier than the large spikes of safety syringes.
3. Find soft flesh. Most popular: belly, hip, butt or thighs. Put those damn fat deposits from lipo to good use!
4. Rotate site of injection to give it time to heal. For example: left belly, right belly, then onward to the thigh.
5. Avoid pokes to the bum if you have to sit for long periods of time.
6. To lessen the pain, first squeeze the fold of flesh and then insert the needle.
7. Avoid shooting into lean muscle, as scarring can happen.
8. Occasionally Fuzeon gets "stuck" in the flesh. When this happens (you'll know it), withdraw the needle and shoot the rest into another site.
9. A hand massage or vibrator can help dissipate the Fuzeon if it stubbornly stays lodged in the flesh.
10. Wear loose clothing to avoid sore spots.
Lesnick's body, too, seemed not to know what to do with the virus-vanquishing liquid. After four months of Fuzeon, his double-digit CD4 count and quarter-million viral load remained unchanged. A stalwart Grossman suggests that Lesnick may be one of a small percentage of patients who researchers now say are "naturally resistant" to the drug. For reasons not fully understood, some 5 to 10 percent of Fuzeon takers have no response -- and the scarier prospect is that such may be their fate with the entire class of entry inhibitors. But for now, Lesnick and Grossman have decided to continue with the experiment; if nothing else, Fuzeon may be keeping his virus from climbing higher.
What about Grossman's other sweepstakes winner, Fred Gormley? At first, he seemed to be on his way to becoming an ideal Fuzeon case study, like Robert Phelps. In the first few weeks, he'd easily endured the mixing and shaking and waiting -- with no nasty injection site reactions. This was partly, he speculated, because of his history with a laundry list of injectables that included insulin, Serostim, Procrit and testosterone. Soon, though, Gormley developed a bacterial infection in one of the ports he used for his amphotericin treatment and later for a feeding tube. The infection consumed his body, and he was rushed to the hospital. There, on the crisp blue morning of GMHC's 17th annual AIDS Walk, his kidneys failed, and Fred Gormley died. "I don't think Fuzeon had had any effect at all by that point," says Grossman. "He was so ill. His body just didn't have anything left to fight with."
THE NEXT GREAT WHITE HOPE
Salvage HIVers learn to live on hope. If Fuzeon disappoints, there's always Roche's second-in-line fusion inhibitor, T-1249. Although research is still preliminary, take-this-with-a-grain-of-salt reports suggest that the drug appears in every way better than its older sibling: more powerful, slower to develop resistance and only one shot a day. Under the care of New York City doctors Ricky Hsu and Paul Bellman, four patients took T-1249 for 14 days and all had what Hsu calls "dramatic" responses: Viral loads close to one million dropped to under 1,000, CD4 counts increased by 50 to 100, and the patients actually gained weight -- in just two weeks! At the end of the two-week trial, however, when the volunteers were switched over to Fuzeon, all but one saw their virus shoot back up to its pre-1249 levels. And the one "success" had started T-1249 with a much lower viral load (75,000 copies) and still had a couple of recyclable meds at his disposal -- another case that may support the idea that Fuzeon works best when taken with other HIV meds that still pack some punch. Roche can't help but have noted the irony: Patients destined to get the most benefit from the drug are precisely the ones least likely to
tolerate its considerable inconveniences.
But that's the best case. For Fuzeon-failed salvagers like John Lesnick and Kat Perera, the urgent question is: Will patients who have developed resistance to Fuzeon get a boost from T-1249? It's too early to tell, but the fact that the region of HIV's genetic code that mutates against Fuzeon is nearly identical to the region that mutates against T-1249 is not encouraging. Joe Eron, MD, of the University of North Carolina, a pioneering fusion-inhibitor researcher, warns that additional sites will probably be discovered as experience accumulates. In test-tube studies, the kissing cousins developed no cross-resistance, but human studies are just now up and running.
Another community worry is that Roche will put the brakes on the development of T-1249 in order to sell as much Fuzeon as possible, never mind that it's the weaker drug.
Roche, of course, adamantly denies such machinations.
It's rough for veteran HIV docs like Grossman, Bellman and Hsu to find a growing number of patients at the end of their treatment rope after six years of "cocktail"-based success. But the most important lesson learned from the protease era is that even the most powerful meds will poop out if not used in concert with other meds to which HIV has not developed resistance. There's every indication that the same is true for Fuzeon. The second-most important lesson learned from the protease era is that the first of a new class tends to be the worst. Say what you will about industry, it has a glowing track record for improving on its successes -- look at king-of-the-PIs Kaletra, Viread or the upcoming PI Zrivada. So who knows? This decade may yet be the era of the entry inhibitors.
"Fuzeon will be an important drug," says Grossman, although he concedes that "it won't have the appeal of a Viread or a Sustiva. The best use will be when you're starting on what looks like your last good highly active regimen, not a crappy, cobbled-together salvage job." But what if the best salvage job you can join up with Fuzeon is crappy and cobbled-together? You may be one of the lucky ones, like Robert Phelps. Or you may not. Then, like Kat Perera and John Lesnick, hanging in with Fuzeon despite little proof that it's working, you'd better find a tender bit of flesh, mix up that solution and -- while you wait for those 20 or 40 minutes of bubble and fizz to end -- count your blessings.
The Fuzeon expanded-access program is closed, but the drug is set for FDA approval this spring. To check on enrollment in Trimeris' 50-person clinical trial of T-1249, call 800.526.6367.
DO ACTIVISTS PLAY FAVORITES
It was just eight years ago that Roche trumpeted that it would be
giving away -- absolutely free -- its new protease inhibitor, Invirase
(saquinavir), to 7,000 HIVers. The drug had yet to be approved by the
Food and Drug Administration, but the need was so dire that Roche was
stepping up to the plate. Activists hailed the company's decision,
especially because the recipients were to be chosen randomly -- by
lottery. Everyone would get a fair shot at this lifesaving med.
This summer, Roche took an entirely different approach when it came
time to administer an expanded-access program for its new fusion
inhibitor Fuzeon. The Swiss pharma giant, which is manufacturing the
drug jointly with small biotech Trimeris, made the drug available only
to 600 patients. And rather than drawing patients' names at random, let
alone widely advertising the program, only well-connected doctors
applied -- and then were chosen on a first-come, first-served basis.
"We made the expanded-access program as large as we could based on the
amount of drug we have at this time," says Roche rep Heather Van Ness.
Even more curious, the same activists who lobbied for a lottery
eight years ago are applauding Roche's decision. In fact, reps from ACT
UP, the AIDS Treatment Data Network (ATDN), Project Inform and other
advocacy groups worked for months with Roche to design the program.
While cynics may accuse the activist elite of stacking the deck so that
they, their docs and their friends -- those in the know -- got first
dibs on the drug, a conspiracy theory is likely far-fetched. According
to most participants, the company simply made a convincing case that
Fuzeon is so time-consuming and difficult to produce, there was no way
to expand the expanded access.
"Roche and Trimeris were really forthcoming," says Ken Fornataro,
ATDN's ED, and a member of the committee that helped design the plan.
"We've been interrogating them for some time about this -- and there's
just no more drug available right now to give out."
Still, the expanded-access plan has left a few activists with a
bitter aftertaste. They charge that Roche and Trimeris should have done
more homework to ensure that more Fuzeon would be ready. "This is
always industry's excuse -- 'You don't understand, this is a new
process, we had to do all these things. Yada, yada, yada,'" says Lynda
Dee, ED of AIDS Action Baltimore. "Well, bull!"