Tibotec Gets AIDS

July 30, 2007

Pharmaceutical Executive

Volume 0, Issue 0

Tibotec is set to launch a second revolution in HIV treatment-­and make a run at Glaxo, BMS, and Abbott, the longtime market kingpins

In the war against AIDS, the chief enemy these days is resistance. Two decades after the first drug, AZT, was approved, there are now 27 HIV medications in four classes, with a first-in-class-five integrase inhibitor due from Merck this fall and several new classes heading for the homestretch. The transformation of this deadly disease into a manageable condition in the developed world has been a stunning achievement—but one relentlessly eroded by the ever-evolving-and-mutating virus. "You've got these patients who did well and you're excited for them," veteran HIV doctor and researcher, Harvard's Jerome Groopman, told the Wall Street Journal last year. "Then you get back with them and they have 12 mutations. You're desperately searching. They're hanging on by a thread."

Year after year tens of thousands of patients in the United States, and countless more worldwide, come to the end of their treatment hope. While statistics vary widely, the average first-line, three-drug combo starts failing after about seven years, while HIV begins to break through second and third regimens after about four and a half and four years, respectively. A decade after the protease revolution literally raised thousands of Lazaruses from their deathbeds, the increasingly urgent need is not simply to disable the virus but to block or even reverse the process of resistance itself.

At this new front, no company is leading more boldly at the moment than Tibotec, a biotech born in Belgium in 1994 and bought in 2002 for $320 million by Johnson & Johnson. With a visionary "resistance to resistance" angle on drug development, the little company is on a big roll. Its first drug, Prezista (darunavir), a protease inhibitor, went from Phase II through accelerated approval last year; now with two non-nucleosides, etravarine, in Phase III, and rilpivirine, in Phase II, Tibotec is set to help launch a second revolution in HIV treatment—and make a run at Glaxo, BMS, and Abbott, the longtime market kingpins.

Glenn Mattes

But if Tibotec succeeds, it will be partly because of its ability to resist another kind of resistance—resistance to the influence and interests of outsiders, most notably patients and the activists who represent them. For if the story of Tibotec is about original science, it is even more about the innovative strategies it has pursued based on the input it got when it opened its doors to a group of people who have traditionally been viewed as pharma's adversaries. Tibotec has focused on the real-world needs of patients, in the process defining the true value of its drugs, winning FDA approval and formulary uptake in near-record time, bucking a trend of price escalation, and, in the words of Martin Delaney, the nation's foremost AIDS activist, acting like "both a scientific leader and a civic leader." As the industry's drug giants scramble to rediscover their lost productivity, their leaders could do worse than learning from Tibotec.

Joining the Resistance

Targeting resistance was the inspiration behind Tibotec. The biotech got its start in a "resistance lab" founded in 1994 by Belgian scientist-cum-entrepreneur Rudi Pauwels. Three years later, Paul Stoffels, an AIDS doctor who did ground-breaking work in Africa before switching tracks to concentrate on HIV R&D at Janssen, teamed up with Pauwels to divide the fast-growing firm into two entities, drugmaker Tibotec and Virco, which had developed the first-ever database of every possible HIV mutation followed by the first-ever diagnostic test for HIV resistance. Immediate demand for the test, which fingers the mutation pattern and drug susceptibility of a patient's virus, was huge because it turned the guesswork of a mortal treatment decision into an exact science.

"Rudi saw the far-reaching implications of resistance before many others," says Roger Pomerantz, MD, president, of Tibotec R&D and the global head of virology. "He and Paul realized that to be true innovators in HIV, they needed to focus on where the medical need would be in 10 or 15 years—and they were exactly right."

When J&J eyed an acquisition of Tibotec, it saw a company with three promising compounds in early-stage development. And tracked as they were toward "salvage patients"—those with extreme resistance who had exhausted all their options—they did not at first glance look like blockbuster material. But crunch the numbers and two trends leap out.

First, the number of salvage patients was (and is) growing at a disturbingly fast clip. Last year, some 40,000 patients in the United States were not responding to even the latest high-power combos, and "20,000 are in dire need," Nelson Vergel, an HIV-positive treatment activist, told the Wall Street Journal last year. "I call them the invisibles because they are too tired and too sick to fight for their rights."

Lew Silbert

Second, any new HIV drug able to lay claim to the market's highest "genetic barrier" (the ability to prevent the virus from escaping the drug's action by mutating) and back it up with proof of competitive potency and durability could deliver a knockout punch to the first-line market leaders: Abbott's Kaletra (lopinavir/ritonavir) and BMS's Reyataz (atazanavir sulfate) in the protease-inhibitor category; BMS's Sustiva (efavirenz) among the non-nucleosides.

So far, drugs used for salvage have tended to be disappointing also-rans. But if J&J won its bet, it would grab a major share of the market in two of the three top HIV classes, while triggering a great leap forward for the treatment paradigm. By combining the diagnostic test with "resistant to resistance" drugs, the far-flung drug empire that was entirely lacking an HIV pipeline could, in one fell swoop, advance personalized medicine as here-and-now, state-of-the-art care in HIV.

But another unpredictable variable quickly came into play in the development of Tibotec's pipeline: the AIDS activists.

A Listening Tour

The medical transformation of AIDS into HIV disease led to the decline of AIDS activism as a mass movement. Gone were the mass demonstrations, the theatrics, the rage, and much of the original wildly anti-pharma attitude. What endured was a network of sophisticated treatment activists who had forged ties with FDA, NIH, and industry's heavy hitters in HIV. Their mastery of the scientific, R&D, and clinical realities of the disease earned them not only respect but considerable clout. By the time the national coalition called ATAC (AIDS Treatment Action Coalition) formed in 2000, every drugmaker had its own history and strategy to deal with the activists.

Tibotec had neither, which proved to be an advantage. Starting from scratch, J&J, with Stoffels' guidance, immediately set about preparing to launch three HIV drugs in as many years. "J&J realized that this was a new space for us—a very interesting, perhaps challenging, space with a lot of opportunity," says Tibotec president Glenn Mattes. "It gave us the beautiful luxury of time to find the right staff and to talk and listen to the community."

Mattes was tapped to build Tibotec after his successful start-over of J&J acquisition Centocor and a long run marketing specialty products in oncology and cardiology. Yet nothing in his experience quite prepared him for this most special of specialties. "None of us who initially thought about this assignment realized the diversity of stakeholders critical to our success," he says.

Mattes faced the challenge head-on. "I decided that it would be very, very important for me to do an awful lot of listening," he says. He took J&J and Tibotec managers to hospitals, public clinics, and AIDS service organizations in and around Newark. The trip was just half an hour's drive from the company's Bridgewater office, but it took them to another planet, populated as it was by the nation's highest proportion of women with HIV, most of them poor, black, and dependent on public funds for treatment and care. "We were staggered by the demographics and the breadth of the disease," Mattes recalls. "It was a quiet ride back to the office."

If Mattes was new to AIDS, two of his big hires were veterans. Alan Tennenberg, MD, Tibotec's vice president of clinical affairs, had started his own public clinic for 1,400 AIDS patients in Jacksonville, FA, where his first order of business was to broker a cease-fire between the department of health and the HIV community. "During my time at the clinic," he recalls, "we brought the two together, and they went from being antagonistic to a nice partnership." Lew Silbert, Tibotec's global vice president of professional affairs, boasted similar stripes. He was at Burroughs-Wellcome when activists campaigned to lower the $8,000 price of AZT. "We realized after four people from ACT UP came in and made themselves comfortable with handcuffs that there was a better way of communicating," he recalls. "I took my cue from that and said, 'Well, why should this be any different than any other human interaction?'"

Alan Tennenberg

In fact, over two decades, the pharmaceutical industry and AIDS activists have alternately fought, exploited, and befriended each other. And when they join forces, as on such issues as streamlining FDA drug approval and targeting public funds for AIDS programs, they make an unbeatable team. "We both want to get the drugs out as fast as possible," says Rob Camp, cochair of ATAC's drug development committee. "Once they realize that, they see that all of our other concerns about patient needs might be worth serious consideration."

Doing Well and Doing Good

This realization was crucial when ATAC and Tibotec sat down to discuss the design of Phase III trials of Prezista and etravarine. The activists proposed that the company step up and conduct the first-ever two-experimental-agent study, a huge boon to salvage patients because it would deliver a double-barreled shot at HIV, while substandard single-drug therapy can be outwitted by the virus with as little as a single genetic mutation.

ATAC had been pushing drugmakers for years to collaborate with each other on such a study, but even pressure from FDA failed to get anyone to bite. Adding a second experimental drug would only double the unknowns and risks; patients would be less safe, trials would take longer, each compound's effects would be harder to clarify—and who needed the headache of sharing proprietary information and other resources with a competitor?

"Here was Tibotec, a company that had two agents of their own that could be tested together," says Heidi Nass, who heads ATAC's drug-development projects with Rob Camp and, like Camp, is HIV-positive. "We thought, If not them, then who?"

Tibotec signed on to the idea not only to serve salvage patients but also to test its two drugs' viability as a marketable combo. Dubbed DUET-1 (Prezista with etravarine) and DUET-2 (etravarine alone), the studies were up and running with 1,200 patients in record time. The typical DUETer had burned through 12 HIV drugs, had extreme resistance, severe immune damage, and was too sick to qualify for most other industry-sponsored trials.

Twenty-four-week results published July 7 in the Lancet showed that 62 percent of patients on the DUET-1 combo had complete viral suppression compared to 44 percent on standard of care, while 56 percent on the DUET-2 monotherapy reached viral undetectability compared with 39 percent on standard of care. Based on these early results, Tibotec immediately filed for FDA approval of etravarine. Data from a second Tibotec study were also unveiled. In a gutsy head-to-head trial pitting Prezista against the leading first-line protease inhibitor, Abbott's Kaletra, in patients with moderate resistance, 70 percent of Prezista patients had undetectable virus after 48 weeks compared with 61 percent on Kaletra. Pomerantz trumpeted the news as "a home run," and Tibotec was set to be the talk of the high-profile International AIDS Society annual confab in late July.

In equally Young Turk fashion, Tibotec is dueling it out for "most powerful and durable in the non-nucleoside class" in a Phase II head-to-head that tests the company's second non-nuke, rilpivirine, against BMS's Sustiva in treatment-naïve patients. At the 48-week mark in March, the two drugs were neck and neck, with undetectability at about 80 percent. But rilpivirine has a distinct edge or two over Sustiva: a higher genetic barrier plus none of Sustiva's disturbing side effects (central-nervous-system havoc and birth defects). In addition, it is a small molecule "perfect for one-pill, once-a-day dosing, and for combining with other medications in fixed doses," says Pomerantz.

Phase II comparative-drug tests are risky for the challenger and, therefore, rare outside of HIV R&D. But FDA applauds such real-world results, and is likely to fast-forward rilpivirine's approval.

Tibotec's arrival on the scene with three new drugs, innovative studies, and glowing real-world data has some analysts buzzing. "If both head-to-head trials succeed for Tibotec, the company will be able to reposition Prezista and rilpivirine as first-line contenders against the current industry leaders," says Datamonitor's Mansi Shah. "This will shake up the market pretty substantially in addition to being a major advance for patients." Prezista, in particular, with its resistance-proof power, has a long shot at even turning the treatment paradigm on its head, allowing for patient-friendly, low-toxic monotherapy, says Ron Camp.

Shah projects that Prezista will hit $850 million in sales by 2015, while rilpivirine's revenues will pass the $700 million mark and etravarine's, $300 million. These "resistant to resistance" drugs, along with Gilead and BMS's one-a-day combo Atripla and the new classes of entry, integrase, and maturation inhibitors, are expected to drive the HIV market up from $7.4 to $10.6 billion by 2015—despite the patent expirations of most of the top-selling products. "Tibotec stands to become one of the leading HIV companies in 10 years' time," says Shah.

The Price of Progress

The acid test of Tibotec's community bona fides came in setting the price for Prezista in 2006.

The pricing of new HIV drugs had come to resemble a game of leap-frog, with the newest hopping over the threshold set by its predecessor with little regard for its likely therapeutic value. In the protease-inhibitor class, for example, Abbott's Kaletra, approved in 2000, cost $9,500 a year; BMS's Reyataz, approved in 2003, $10,900; and Boehringer-Ingelheim's Aptivus (tipranavir), approved in 2005 and widely viewed as underwhelming, $13,600. Tibotec initially announced that it would embrace the model, pricing Prezista at $18,500 a year, higher even than the priciest HIV drug, Fuzeon (enfuvirtide)—an injectible entry inhibitor that is many salvage patients' last resort.

Activists, angling for a dramatic reversal of the trend, drew a line in the sand at Kaletra's price tag, a full 50 percent below the company's target. "There was a feeling that the community had dropped the ball on Reyataz and that now we had to make a stand," recalls ATAC's Nass. It was another case of asking Tibotec, "If not you, then who?"

A letter to Glenn Mattes signed by 400 AIDS organizations, advocates, and patients explained the community's perspective. What was at stake was more than the price of a single drug. With the cost for one year of triple-drug therapy now averaging more than $15,000, a patient with HIV can expect to pay—or hope that public or private insurance will pay—about $2 million for every decade of life. Multiply that by 550,000—a rough estimate of the 1.1 million Americans with HIV who currently need medication—and the costs of HIV drugs in the United States alone will easily exceed a trillion dollars over the next 50 years. And it's far from certain that a healthcare system already in crisis will continue to bankroll life-saving treatment for a preventable disease still widely perceived as the wages of immoral behavior.

There was no uncertainty about the carrot and stick being held out to Tibotec by what was, in effect, the product's entire audience of key opinion leaders and specialists. Charging a "fair" price would set the stage for a primo Prezista launch, while "Most Expensive HIV Drug Ever" headlines and charges of price-gouging could relegate the drug's benefits to the fine print.

Not that the activists were unsympathetic to Tibotec's position. Says Ness: "They had to go back to J&J and say, 'You know that drug we keep telling you is so great, and it's our first one and all, well, guess what? We don't want to price it very high.' That is not a pleasant meeting to contemplate."

As for Mattes, he had his company run its own health-economics modeling—"these exquisite pharmacoeconomic analyses describing beyond any doubt the actual value of our product relative to others." Armed in this way, says Silbert, "we got people to sit down and have an intellectual discussion rather than an emotional one, since pricing is so emotional."

Mattes says only that once his bosses at J&J understood the particular context and history, they gave their full support. Silbert allows that "we had to do considerable internal politics to get it down to 'Let's set a precedent. Let's not be the next one to price up.'"

So when Tibotec announced that the price for Prezista would be $25 per day—$4 less than Aptivus and only a quarter more than Reyataz—the community lined up to kiss the company in the press. Formulary inclusion by public and private payers has been swift, while Tibotec's sales force is boning up on the arcana of resistance, genotype and phenotype, and the non-nuke class's notorious K103N mutation to which etravarine and rilpivirine are immune. "We set a pretty ambitious goal for ourselves in terms of time and percent of patient lives that would be covered for reimbursement," Mattes says. "And so far we've actually exceeded them."

In April, Tibotec signed an agreement with Aspen to distribute Prezista in sub-Saharan Africa at a price of $3 a day. "It's extremely gratifying to be involved in developing Prezista and helping people understand how to use it," Tennenberg says. "I can think of patients who could have benefited from this in my practice had only it been available six, seven years ago. But at least now my contribution is magnified by every doctor and every patient who gets the drug."

A Peek in the Pipeline

Not all the action at Tibotec centers on HIV. Its pipeline contains compounds for hepatitis C and extensively drug-resistant tuberculosis (XDR-TB), both of which happen to be common coinfections and killers of people with HIV worldwide. Although the hepatitis virus shares many molecular similarities with HIV, HCV research has lagged until recently. As for TB, treatment for this neglected developing-world plague has scarcely advanced in 40 years.

In April, the first protease inhibitor to treat HCV, telepravir, which Tibotec is codeveloping with Vertex, made news because in a large Phase IIb trial it cut treatment time in half when taken with the standard of care. This promises a critical advance because hep C requires a 48-week course of treatment, and the often-brutal side effects make compliance difficult. The company is also working on a polymerase inhibitor that could be taken in combination with telepravir, on the HIV regimen model. In July, Tibotec signed two new license agreements with Medivir for a Phase I polymerase inhibitor for HIV and hepatitis B as well as a preclinical HIV protease inhibitor.

Tibotec also just started a Phase II trial of TMC 207, a novel molecule that has shown potency against a slew of resistant TB strains, including XDR bacteria—the "untreatable" type (mis)diagnosed in the globe-trotting young Atlanta attorney in June. If TMC 207 pans out, it could save a million lives in the developing world and put the brakes on the runaway epidemic of resistant TB.

On the drawing board is a novel trial design to treat patients with both hep C and HIV using new Tibotec drugs for both viruses that have shown minimal interactions. Since coinfected patients currently must choose between treating their HCV or their HIV, a combo targeting both that was both safe and effective might erase hepatitis C's dubious distinction as the number-one killer of US HIV patients.

Says Julie McHugh, J&J's company group chair of virology: "We place a high priority on early collaboration between the R&D and commercial sides, strategizing around not only how to bring a product to market but what are the data sets that make a difference to physicians and patients."

Captured Alive

AIDS, of course, remains the mission. Tibotec is currently conducting the largest-ever trial of HIV treatment in women. "The typical industry-sponsored study is at least 80 percent male, and most are white, so there's a need to know how the drugs perform in women," says Tennenberg. "When talking with the community about how we could study Prezista in a way that would both meet people's needs and help us understand how it worked best, we all agreed that a study in women and minorities makes sense."

And the company's relationship with activists and patients continues to deepen. In a sign of the trust the community has invested in Tibotec, the National Association of People With AIDS invited Glen Mattes to become only the second member from pharma to join its board. Like many activists, Mattes fears for the future. Will our nation continue to budget the billions of dollars necessary for adequate HIV treatment and care? Will the movement, founded and largely fueled by gay white men but increasingly peopled by African-American women, transcend its many differences to fight another day? "We have to be careful that all the hard work that's been put into distinguishing the needs of this population continues to have a champion," Mattes says. "And I think there's an opportunity—whether for the industry or our company—to be an integral partner in that."

One recent development, however, threatens to complicate, if not scuttle, the hard-won relationship between activists and pharma. The Office of Inspector General is stepping up enforcement of regulations against direct communication between drug makers and patient groups. Nass notes, "A few companies that have been receptive to us in the past are now telling us that their lawyers are telling them that they can't meet with us because the government will look at it as the company trying to improperly influence the patients."

The unintended consequence of the OIG's crackdown may be to curtail the influence groups like ATAC have in helping prioritize the complex reality of patient needs in drug company's decision-making. For now, the pharma-activist alliance still has friends in high places. "FDA has said that they support the community meeting with industry, even though the OIG may oppose it," Camp says. "They really believe that getting drugs approved quickly and introducing innovations into drug development are very important." But it remains to be seen whether this special relationship based on mutual influence and interests will escape the changing political weather inside the Beltway.

On the day in June 2006 when he got word from FDA that his first drug had been waved through, Glenn Mattes says, "after the obligatory internal discussions and media contacts, I made calls to all the activists and community members to thank them for their support. And I said, 'Let's really use this day to springboard our working relationship forward.'" He was surprised to learn that it was the first time in 20 years that the president of a drug company had made such a call to activists.

"In HIV, I'm closer to the actual patient than I have ever been before, even in cancer," Mattes says. Many AIDS advocates, of course, have HIV, and many physicians are AIDS advocates, and on it goes. "That makes it very special," he says. "The community spirit, the personal commitment and passion, either that captures you or it doesn't." He pauses and laughs in spite of himself. "And I can certainly say it captured me."

Tibotec has even invested in a long-shot gene-therapy experiment to produce a line of immune cells that are themselves immune to HIV and its effects. This approach has been kicked around casually for more than 15 years, but Tibotec's is the single serious study up and running. In fact, Tibotec, along with Merck, is the only company in all of pharma looking for the cure.