American Foundation for AIDS Research, August 2003
Kristen Kresge

Analysts were startled when Bristol-Myers Squibb (BMS) announced two years ago that it was acquiring DuPont Pharmaceuticals for $7.8 billion. Rumors circulated among investors that the purchase price was nearly $2 billion more than the next highest bid. It was not clear how Bristol expected to recoup this large an investment. That question looms even larger now: Bristol has abandoned DuPont’s entire stable of promising new HIV drugs one after the other. The takeover’s net result so far has been to increase Bristol’s marketing prowess by enlarging the range of “once daily” HIV drugs Bristol offers while killing off the potential new competition represented by DuPont’s experimental agents.

Falling by the Wayside

DuPont was a minor player in the pharmaceutical world that established itself through the rapid development and marketing of its HIV drug efavirenz (Sustiva). The aggressive work of DuPont’s small research team was something BMS needed to energize its struggling laboratories, and Bristol early on proclaimed its interest in adding the DuPont scientists to its organization.

DuPont brought with it a particularly rich pipeline of experimental HIV drugs. The company had an active clinical program developing all three standard HIV drug classes: protease inhibitors, nucleoside analogs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of these “second generation” compounds had already entered clinical trials and held promise for treating drug-resistant virus.

But Bristol already had its own HIV drugs to promote. The nucleoside analogs d4T (Zerit) and ddI (Videx) were consistent big sellers and are available in new once-a-day forms. There is also a once daily protease inhibitor, atazanavir, for which Food and Drug Administration (FDA) approval is now imminent (see accompanying article). By adding once daily efavirenz to this trio, Bristol obtained a complete range of HIV drugs for combination therapy and could immediately challenge GlaxoSmithKline for dominance in the HIV market.

How BMS would take advantage of DuPont’s candidate HIV drugs was a subject of speculation. In the best of times, Bristol’s record of drug development has been less than stellar – it took the company seven years to bring atazanavir to market after purchasing it from Ciba-Geigy (now part of Novartis). Observers feared that the new DuPont drugs would also get bogged down, or even suppressed altogether, by the pressure to show immediate income from the DuPont acquisition as well as by marketing considerations. Although the new drugs may not be groundbreaking new options, delaying them could be a huge loss to the growing number of people with multidrug-resistant HIV.

Bristol officials at first maintained that the DuPont second generation NNRTI, DPC 083, could come to the market in 2003, helping those for whom efavirenz and other NNRTIs no longer work. But DPC 083 is nowhere to be seen, and DuPont’s other experimental agents have also quietly fallen by the wayside.

The effort to expand Bristol’s research team also quickly faded. Layoffs at DuPont began shortly after the acquisition in departments outside of research and development, but no department was spared. Last November, Bristol announced it was closing all of the former DuPont sites in Delaware and dismissed most researchers at these sites.

“The only thing they took from DuPont was Sustiva,” said Dr. Michael Otto, Chief Scientific Officer of Pharmasset, a small research company in Georgia. “They kept virtually none of the people.” Otto worked in the virology program at DuPont for ten years and knew many of its members.

The First to Fall

The first promising drug abandoned by BMS was DPC 817, a potent nucleoside analog that was in phase I trials. This compound was licensed by DuPont, along with a family of other compounds from Pharmasset, an Atlanta biotech founded by noted HIV drug creator Raymond Schinazi of Emory University.

After buying DuPont Pharmaceuticals, several Bristol executives gathered at DuPont’s Wilmington, Delaware site to hear presentations by members of the virology team on the status of their pipeline. The DuPont staff was told not to bother with DPC 817. Bristol already had two nucleoside analogs, and it was not looking for others. “It was announced that they weren’t interested,” said one DuPont virologist present at the gathering.

Shortly after deciding on the acquisition in the spring of 2001, Bristol decided to return DPC 817 to Pharmasset. Yet at a community meeting in February 2002, officials from BMS reported that DPC 817 was dropped due to animal toxicity.

“That is a lie,” said Otto. In fact, after the drug’s return to Pharmasset, Otto and his company continued with development and restarted human trials of their own. Otto does acknowledge that the drug is not tolerated in rats, but he says that no obvious safety issues have yet arisen in humans.

BMS now seems to agree with Otto. In a recent interview, Brian Henry, the Associate Director of Virology in Corporate Affairs at Bristol, said the reason for returning DPC 817 to Pharmasset was a business decision based on a “very robust” BMS portfolio. Henry would not comment on any previous reports of the drug’s toxicity.

Single doses of DPC 817 in treatment-naïve volunteers resulted in a mean 0.44 log (64%) drop in HIV viral load. Pharmasset says it is developing this drug (now dubbed “Reverset”) primarily for salvage therapy based on its in vitro effect on HIV with drug-resistance mutations.

Prioritizing its own Protease Inhibitor

Bristol also quickly stalled DuPont’s early-stage protease inhibitor program. Before the sale to BMS, two second-generation protease inhibitors (DPC 681 and 684) completed phase I trials. Although these compounds were not pursued, their progress spurred a further attempt to find protease inhibitors similarly active against HIV with resistance to current protease inhibitors.

In the introductory talks between DuPont virologists and BMS executives, little time was reserved to discuss the status of the five-year, 50-person protease inhibitor program. Five minutes, to be exact. “The impression was that they had a PI [atazanavir] so that was of less interest to them,” said the DuPont virologist present at the meeting.

Bristol has remained focused on atazanavir and has for now, overlooked DuPont’s candidate protease inhibitors. No official statement could be obtained as to their current status.

The Bigger They are, the Harder They Fall

The most difficult and complicated story of the DuPont pipeline is DPC 083. This drug was chosen as the lead compound to back up efavirenz. Resistance mutations that severely limited the potency of efavirenz were less likely to impact 083. Activity against resistant virus made it a promising new compound and hopes were high for its success at Bristol.

Prior to the DuPont sale, two phase II trials with 083 were in progress (DPC083-201, and -203). The 203 study faced a multitude of complications. Many sites were unable to enroll the required number of participants due to the strict entry criteria. To accelerate enrollment, DuPont officials began changing the study protocol while the trial was in progress. The maximum allowable viral load at entry was raised from 5,000 to 10,000 copies/mL – a more common viral load cutoff – halfway through the study.

But enrollment in the study lagged even after the raising this limit. Controversies surrounding prior drug experience and eligibility for the trial arose on a regular basis. Study coordinators were on the phone with DuPont officials daily trying to enroll seven or eight volunteers.

The planned study size was 150, equally divided between the 100- and 200-mg doses. The 200-mg dose was evaluated only in Europe because the US FDA had safety concerns about this dose. The total number of volunteers ended up at 31. With so few participants, it became difficult to extract any useful data.

“This was the most poorly written protocol that I have run. Things started popping up after the fact, and we were losing touch with hard science,” said a staff member at one study site.

Yet none of these problems surfaced until after Bristol took over. The staff member speculated that the quality of the 203 study was affected by staffing changes that occurred at DuPont as the official sale date approached.

In study 203, 45% of the volunteers (14 of 31) were expelled because of protocol violations. The problem was these volunteers had prior protease inhibitor therapy, which, according to Bristol, made them ineligible. There is still some confusion here. The trial site staffer insists that official protocol only excluded people who dropped their protease inhibitor because of HIV breakthrough.

But Bristol remained publicly committed to 083. It did appear overall, from this and other studies, that 083 was a potent drug with a safety profile similar to efavirenz. Rash appeared to be worse but the efavirenz-associated effects on the central nervous system seemed less prevalent.

Even if this phase II study was completely bungled, it need not be the end of DPC 083. In an oral presentation at the 2002 Conference on Retroviruses and Opportunistic Infections, Bristol (and ex-DuPont) researcher Nancy Ruiz stated in her conclusion that a new phase II trial was “in planning.”

Then development of 083 was halted without public announcement. “Currently we have stopped development of DPC 083. We are not moving forward,” Henry confirmed this spring. He said that Bristol dropped 083 simply “because efficacy in NNRTI failures was not established.”

Ruiz had told some clinicians working on the 203 study that another of the four NNRTI candidates would be explored, but at least one of these doctors deems it unlikely. BMS would not confirm any work on other NNRTIs.

Don’t Get Your Hopes Up

“BMS had a different niche. We were geared towards second generation compounds,” commented Susan Erickson-Viitanen, former Executive Director of Virology at DuPont Pharmaceuticals. “We thought Sustiva is a good drug – what will we do next?” Viitanen sees Bristol focusing more on new drug classes in the future. “Their entry inhibitor is a totally new thing,” she noted.

Bristol’s new entry inhibitor has an unproven mechanism of action and remains in very early development. Although Bristol representatives have stated that commitment to their HIV program remains strong, the company may have squandered DuPont’s more advanced improvements on conventional HIV drugs. Bristol is now mired in financial scandals, involving exaggerated profits, and its stock price has plummeted. Its financial decline threatens any hope that the DuPont compounds will see the light of day. Now, more than ever, Bristol is inclined to protect the profits from its established drugs.

In the aftermath of Bristol’s weakened position, rumors of the company’s sale to GlaxoSmithKline surfaced this spring. The rumors were based on the apparent “fit” between BMS and GSK products. But Bristol’s handling of the DuPont acquisition, and its adverse consequences for those with HIV, is a warning against concentrating research and marketing muscle in one giant corporation.

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