This month marks the one-year anniversary of the FDA licensure for T-20 (Fuzeon). The much anticipated and storied therapeutic received universal acclaim, as did its sponsor, for innovation and perseverance. Following a tortuous and sometimes controversial clinical development, the first in a new class of antiretrovirals generically lumped together as entry inhibitors, fêted its official launch at the IAS conference in a sultry Paris last July. And despite prolonged clamoring of shortages and lavish predictions of early blockbuster status, uptake proceeds at a moribund pace—and Trimeris finds itself not awash in cash but flummoxed by a vanishing "footprint" and soaring marketing expenses. One year on, rather than their barn storming potion flying off the shelves like the better built mousetrap it was billed to be, they find themselves sitting on warehouses full of the stuff, fretting about how much they're now going to have to spend to turn the tide. Mike Barr prepared this special report for TAGline.

It may seem ages ago that activist outrage at the production limitations (and usurious price) of the much anticipated T-20 erupted. Resourceful physicians called in their chits with those in positions of power in order to ensure supply as Fuzeon distributor ChroniMed first rolled into town. And in anticipation of Medicaid snafus and red tape, ADAP coordinators urged physicians to place orders for the drug well in advance of actual prescribing decisions. Such was the fury of Fuzeon. A text book case of triumphant "expectations management" on the part of the Trimeris/Roche marketing team.

At the July International AIDS Society (IAS) conference in a sultry Paris (where later it was discovered that over 10,000 "plus âgés" died of the record heat while ER staff were sprawled out on Mediterranean beaches or cooling themselves in quaint alpine villages), 2003 was trumpeted as "the year of Fuzeon." And according to even the most conservative prognostications, Fuzeon was set to become the true billion dollar drug—a milestone which had eluded the eponymous molecule of Vertex/Glaxo years earlier (see Barry Werth, 1994).

Great furor ensued when, shortly after its U.S. FDA approval, Trimeris/Roche announced there would be sufficient quantity of drug for only 8,000-10,000 of the neediest cases—down from an earlier announcement of 12,000-15,000. Four months later the company had curiously reversed itself again, saying it would have drug enough for 18,000 patients worldwide—and expected to be able to expand that to 24,000-32,000 in 2004 and 40,000 in 2005.

Looking back, this all may seem a little absurd. For as of year-end 2003 the company had provided Fuzeon to all of 4,350 patients—and actually sold it to fewer than 4,000. (Some 1,300 Fuzeon "kits," approximately 430 patients, were distributed via the Trimeris Patient Assistance Program or "PAP" and thus need to be subtracted from the raw sales figures.) And with a 25% "early terminator" rate (patients who unexpectedly discontinue the drug within the first 1-2 months), that number was expected to fall significantly (to somewhere around 2,800 patients) by the time the ink had dried on the quarterly report. From Trimeris predictions of 8,000-10,000 patients on Fuzeon by year-end 2003, the stark reality was that they had fallen short by over half. 2003 sales figures, initially estimated at $120 million—and expected to peak around $1 billion, came in at a mere $36 million. The question on everyone's mind: what went wrong?

In six short months the Trimeris/Roche team has alienated its former Wall Street champions, furloughed a third or so of its North Carolina research staff, terminated a relationship with its principal distributor (ChroniMed), liquidated what remained of its R&D portfolio and lost a cool $860M in market cap in the process. Greed may be good, Gordon Gekko, but the Trimeris story nearly renders comprehensible the old saw about shooting oneself in the foot to spite one's face.

On a more practical level, the pity here is that most of Trimeris' misfortune was entirely avoidable. And while it is tempting to bask in the bittersweet revenge that appears to have wrought havoc on Trimeris/Roche's quick road to riches, Trimeris' failure is good for virtually no one. An entirely unsuccessful product launch of the first HIV therapeutic with a truly novel mechanism of action would likely send shock waves through the entry inhibitor portfolios of other upstarts. Still, there are clearly lessons to be learned—and then not repeated. One may never know for sure how pricing and early access decisions were made—how real the supply concerns, how costly the drug development—but in retrospect these two decisions appear to have been pivotal.

A real expanded access program may have helped them to avoid the most serious problems they now face: physician comfort with prescribing the drug, broader patient "uptake," and nursing support. While it may have risked exposing too many "real life" salvage patients to a product that was shown to shine in the fastidiously managed TORO studies, this was probably a bet worth wagering. Even if a bit of the buzz had been beaten back by a Fuzeon failure story here or there, an ample expanded access program early on would have also "cleared the deck" of the neediest cases and paved the way for a more ecstatic word of mouth once the product was actually on pharmacy shelves. In this respect at least, the 25% early discontinuation rate which Trimeris has experienced since launch need not have been so high.

Then, of course, there is the issue of price. Eyebrows will always be raised when the price of a desperately needed new therapeutic comes in at just a few thousand dollars above what the market currently bears. Cynical suspicions aside, one cannot help but wonder if it might have been a better idea to sell more drug at a lower price rather than the decision that was in fact made: price it sky high (on the cusp of a huge economic downturn and record low tax receipts for states, no less) and be forced to suffer the sluggish indignations of form filling and administrative sign offs in order to get it paid for. Even pharma circuiteer Dr. Robert Murphy conceded recently that a full half of the patients who actually want to take the drug (and even might continue to take after the first couple of months!) simply cannot get it.

During the course of an early February conference call, Trimeris CEO Dani Bolognesi outlined Trimeris' plan to rescue their salvage therapy. "During the initial stage of this launch we have learned a great deal about the issues facing this unique drug and look forward to seeing the results of our heightened marketing initiatives on the uptake of Fuzeon in 2004," he conceded to a group of investment types on February 3rd. Overall, the plan calls for huge increases in sales and marketing expenses—costs which certainly could not have been anticipated just six months ago. They include the following:

1. Firing ChroniMed and establishing a multi-vendor distribution network.
   
   
2. "Heightening awareness" of Fuzeon through "compelling" advertising and promotional campaigns. These print and internet campaigns directed to patients, clinicians, pharmacists, nurses, and treatment educators will be implemented across the United States throughout 2004 and are "expected to continue in various forms beyond that time."
   
   
3. Dispatching bands of Fuzeon trained nurses to the 20 or so principal Roche sales regions across the country in order to try to turn the tide of early terminators. The Fuzeon brigade will travel to physicians' offices and patients' homes to assist in the administration of the drug. (One can imagine the Cuckoo's Nest scenario: "By god, you're gonna take this drug even if I have to tie you down and inject it myself! And while we're at it, maybe we'll call in a few refill requests…")
   
   [For the record, AAHIVM board member and leading New York AIDS doc Howard Grossman cautions against lampooning the visiting nurse initiative. "It's not about tying patients down," he argued. "We've seen a lot of patients come through for studies, referred by other docs, who never got good teaching on injections. A bunch of them were handed the video and told to watch it and then do it. Of course, they're having problems, increase injection site reactions, et cetera and quickly going off the drug. We're finding that re-teaching people has some real benefit."]
   
   
4. Setting up so-called "out-bound" call centers. Basically, a telemarketing squad (think "Indirectly Observed Therapy" (IDiOT)) assigned the task of personally following up with all current, new and waffling Fuzeon patients (upon their assent) in order to assure that doses are not missed and that prescription refills are not delayed.
   
   
5. "Upgrading" the Fuzeon patient mix. Put simply, Roche would like to move Fuzeon one or two steps up the treatment chain: so that docs would use it as part of a 2nd or 3rd line regimen—and not wait until a salvage or deep salvage situation. SG Cowen & Co. biotech analyst Yaron Werber, in a 26-page September report observed that, "A key factor in Fuzeon's prospective growth will be Trimeris/Roche's ability to move beyond usage solely in deep salvage patients—[but instead] to include those triple-class experienced patients most likely to benefit from Fuzeon therapy."

In a way, just such a change in Fuzeon patient "mix" would probably more closely mirror the vaunted TORO study population. The problem with this strategy, of course, is that HIV+ people who are leading relatively normal, active, mobile (pain free?) lives are unlikely to agree to the quality of life constraints twice daily Fuzeon administration entails. It's the paradox of the entire Fuzeon program popping up, again and again: those who are most likely to benefit from the drug are the least likely to take it. Trimeris/Roche have at least three post-marketing clinical trial designs in the works. The highest priority for them (ready to go this spring, they say) will be the trial which attempts to strengthen the case for their new strategic positioning.

All this and a little sleight of hand (the company has expressed its wish to switch from counting actual patients on treatment to counting Fuzeon kits shipped—an accounting artifice which tends to pad the otherwise conservative IMS Health sales figures) may succeed in reversing the current downward business trajectory. But the key issues—price and formulation—do not appear to be part of the Fuzeon rescue plan.

Looming in the distance is a twice spurned Roche family that could at any time decide to cut its losses and run. Partnership deals are apparently renewed one year at a time, and Roche has made its carrying of a large part of Fuzeon's sales and marketing costs (all but $10 million of the $66 million for basically nine months of 2003—nearly half that in the 4th quarter alone) contingent upon certain undisclosed "sales milestones"—an arrangement not uncommon in this kind of agreement. Sales and marketing expenses for 2004 are expected to continue to expand (approximately $80-90M), as Roche launches a re-election style marketing blitz in addition to the outbound call centers and nomadic nursing teams. (Get a load of the latest Poz supplement: "Take Your Best Shot.")

If Dr. Bolognesi is worried, he certainly didn't show it on the February conference call. Every setback on the analysts' laundry list of problems and disappointments was greeted enthusiastically by Bolognesi as yet another "opportunity." And when cross examined by a very much engaged Yaron Weber about Roche's near-term commitment to this product, Dani was similarly unfazed: "Roche continues to express their commitment to this product. They believe that Fuzeon will establish its rightful place in the treatment of experienced patients as we've said here today. They believe strongly that they can overcome the issues that are out there in the marketplace in the early phases of this launch. These guys are in it for the long haul." We wish them well. ¤

In an attempt to balance last month's immune-based pipeline update which might have been a bit heavy on cytokine therapies and other immunologic esoterica, this month we feature a more conversational approach to what some see as the holy grail of IBT research: a therapeutic vaccine, most likely administered on a (very) infrequent basis, that would render life-long antiretroviral therapy anachronistic.

TAGline: I couldn't help but notice that while you included quite a few therapeutic vaccine candidates in your immune-based therapies table, they weren't mentioned within the text of your report. Personally, I've been regaling friends for the past six years or so with stories of how a therapeutic vaccine would arrive on the scene and save us from these nasty antiretrovirals. You're making me look bad!

RJ: I sort of scrunched the therapeutic vaccines all together just because the basic principle behind them is the same and I was a bit worried about space.

TAGline: And also because you've lost faith in the biological rationale?

RJ: No, not at all. There have been major advances in basic T cell immunology which firmly support the rationale for trying the approach which I think is very important. Brigitte Autran, specifically, has just recently gone on record as very optimistic. A lot of other researchers remain skeptical, though.

TAGline: Advances? I confess I'm a bit behind in my European Journal of Immunology reading. What advances exactly?

RJ: Basically, HIV-specific CD4 T cells seem to get sort of stuck in a pre-memory state in all but long-term non-progressors, so untreated progressive disease is like a sort of persistent, low-level acute infection.

TAGline: So an effective therapeutic vaccine then would, what, wake up a "post-memory" immune system?

RJ: In a manner of speaking. Most of the T cell activation that accompanies uncontrolled HIV replication may be the result of naïve T cells getting activated, not memory T cells. Activated naïve T cells take several weeks to mature into memory T cells with characteristic, and potentially important, functional properties such as IL-2 production and proliferative capacity, and this rarely seems to happen in untreated HIV infection. Creating a more functional HIV-specific memory T cell pool has become the goal of many research teams now—including Autran's.

TAGline: Is there any precedent for this? I guess I mean, any evidence that this is even achievable?

RJ: When HAART is initiated, you do see evidence that some activated T cells complete their differentiation into IL-2-producing "central memory" HIV-specific CD4 T cells, but the numbers remain below that seen in long-term non-progressors. The data comes from Guisseppe Pantaleo's lab, although I'm putting a froth of speculation on top.

TAGline: This is getting heavy. Let's go for a bottom line here.

RJ: Bottom line: A good vaccine can almost certainly help increase the numbers of these [IL-2-producing "central memory" HIV-specific CD4 T] cells, hence potentially better preparing the immune system to control HIV when HAART is stopped. Whether this pans out, of course, remains to be seen.

TAGline: So, wait. We're back to HAART followed by treatment interruption followed by a therapeutic vaccine? Why not just the vaccine—from the get go?

RJ: What seems to inhibit the differentiation of memory T cells is persistent viral replication, so vaccinating in the setting of uncontrolled viremia is unlikely to generate the sort of memory response that people are after. Immunizing while an individual is on HAART—and allowing enough time for the memory T cell response to develop or "mature"—looks like the better way to go. One concern I have about many current studies is that the timing of immunizations and HAART interruptions may be too concentrated to allow this maturation process to fully complete. For example, many protocols have used monthly immunizations and/or interrupted HAART just a few weeks after the last immunization. According to basic immunologists, intervals of at least three months would be a lot better. Quite literally, developing memory T cells like a nice long rest before going into action.

TAGline: I'm trying to recall your chart on this. You mentioned Merck and Glaxo, but the Glaxo product hasn't even been in humans has it? Seems Aventis is furthest along, but isn't that the ALVAC vaccine that failed in preventive studies?

RJ: ALVAC is in a few therapeutic studies, but hasn't shown much promise. The first ALVAC efficacy trial as a preventive just got underway, although the inclusion of AIDSVAX as a booster is a big problem. Glaxo's construct is in phase I as a preventive, but I don't think therapeutic trials have started yet. There are therapeutic trials planned through the ACTG for Merck's adenovirus-based vaccine (phase I/II), a DNA construct made by the NIH's Vaccine Research Center (phase I) and RIGHT's Dermavir (pre-clinical) constructs which I can detail a bit more since they will be open around the country and potentially, uh, joinable.

Therapeutic Vaccines Candidates mentioned in this article (adapted from February TAGline table)

TAGline: So, big picture, the science is ripe. What needs to happen, then, to accelerate the development of something we can use?

RJ: I think the major issue in terms of IBT incentives now is not any longer the unknowns, but rather the potential competition with the lucrative market for antiretrovirals.

TAGline: Are we talking cannibalism-phobia here?

RJ: Otherwise know as fear of shooting yourself in the foot with something that may be good for medicine but bad for business. Truth be told, an effective therapeutic vaccine would ideally reduce reliance on drug therapy, and—to get in touch with my inner conspiracy theorist—it's possible that this makes the approach rather unpopular with members of the Retrovirus mafia who have nice cozy relationships with the big antiretroviral manufacturers.

TAGline: Meaning we can only expect an effective immune-based therapy or therapeutic vaccine if it doesn't cut into Big Pharma's other sales? Lovely.

RJ: Well, maybe. Also, immunological principles suggest that a good therapeutic vaccine should not have to be administered chronically, and this isn't the sort of thing Big Pharma is very fond of developing. Look at the history of drug development for other life-threatening illnesses: a one-shot cure is the last thing you want—unless perhaps you can charge millions of dollars a pop for it. Where Big Pharma is concerned, chronic daily dosing of expensive medication is much more rewarding.

TAGline: I guess that means the best immune-based therapy for Big Pharma would be one that doesn't really work? Then we're screwed, basically. Unless some Deaniac outsider upstart can come in a trail blazing and take on the big vested interests?

RJ: Merck sort of seems to be taking the high ground in pursuing their construct—in the odd way that Merck does sometimes. There is also an emerging movement towards re-evaluating approaches to R&D so that, when market forces and good medicine clash, other mechanisms can fill the gap.

TAGline: An emerging movement. I like the sound of that. Sounds similar to something Paul Bellman approached me about recently. Might make for an interesting future TAGline article. And what of the other big players? Glaxo? Wyeth?

RJ: I suspect that GlaxoSmithKline has just jumped on the therapeutic vaccine bandwagon. I'm skeptical as to whether they really intend to take their product the whole way. It's a pretty shitty immunogen. Wyeth has some DNA+cytokine adjuvant constructs that are likely to be studied as therapeutics.

TAGline: And what about my white knight scenario?

RJ: Yes, of course. The more optimistic flipside to all of this is that the small biotech outfits could potentially make money from this sort of approach more easily than the bigger companies—and may therefore be more likely to step in now that the basic science is giving them some reason to think that therapeutic vaccines (and perhaps some other immune-based therapies) could provide sufficient benefit to be licensable.

TAGline: Blessed are the lithe and the big risk takers. ¤

Last year's pipeline report was warm and hopeful and excited. How wrong can one reporter be? The close of the year 2003 saw the "on-hold"-ing of SCH-C, the entry inhibitor that was moribund before the ink on the articles describing it was dry. According to Schering-Plough, it will remain sidelined while SCH-D goes forward. And unless something more vicious than arrhythmia comes up with SCH-D, SCH-C is not expected to be resurrected.

Roche gave us the end-of-year blues, dropping T-1249 due to "viscosity issues". (It mysteriously became a lot more viscous after the disappointingly thin sales numbers for T-20: by the end of the year 2003, they were struggling to come up with proof of even 4,000 people on drug world wide.) In order to dedicate more time and effort to selling T-20 (it wasn't getting ordered by itself; remember, two subcutaneous shots a day at $20,000+ a year), they apparently couldn't devote any additional resources to T-1249.

Both integrase inhibitors have been fossilized and won't be moving forward: The Glaxo/Shiniogi compound S-1360, greeted with much synergy fanfare last year, was formally announced gonzo. Glaxo is making sounds that they have other integrase in the wings, but there is nothing to report on yet. Merck has been the forward leader in plotting the integrase gene and understanding its être. They report no news on either of their two L- compounds (L-870,810 and L-870,812). Either they are restructuring their HIV division now that Dr Emilio Emini has left, or one of the reasons that Emini left is that there was nothing exciting to move forward. "We'll have to wait and see" is how I ended last year's report. We're still doing so, at least with Merck.

So, of the seven drugs highlighted in TAG's summer 2003 pipeline report, four are dead in the water. Luckily, a new protégé of GSK (along with a previously obscure BMS compound) appeared out of virtually nowhere to cushion the pain. Next month's TAGline will feature a reluctant indulgence of the latest line-up of me-toos. Stay tuned. ¤ -RC

† Launch projections are not part of Rob's report but gleaned from industry reports. --MB