Genta's Clinical Quest

In one of the biggest late-stage biotech licensing deals ever, Genta has given Aventis worldwide rights to Genasense. The antisense compound targets Bcl-2, a protein now known to protect cancer cells from death messages. The firms are betting that giving patients this compound in combination with conventional therapies will kill cancer more effectively. The potential is high, but risk remains. Bcl-2 is unproven as a target, and designing clinical trials for two agents is not straightforward. Emerging from a troubled past, Genta initially decided to take the compound to market in the US all on its own. It focused on helping desperately ill patients in small disease indications. Eventually, as encouraging data accumulated, the small firm realized it would be better off partnering. The focused indications that Genta chose, and the way it pursued them, made strategic sense for it-but Aventis aspires to develop the drug against major cancer cancers. The large firm can afford to think bigger: it has more money and resources and the benefit of coming in after Genta laid the groundwork. Both companies are being guided by theories and observations, fully aware that such things mean little to regulators who demand clinical evidence. As befits their respective size and scope, the firms have different approaches to managing the risks of novelty.

Genta and Aventis are working to commercialize Genasense for cancer. As befits their respective size and scope, the firms have different approaches to managing the risks of novelty.

by Deborah Erickson

• In one of the biggest late-stage biotech licensing deals ever, Genta has given Aventis worldwide rights to Genasense. The antisense compound targets Bcl-2, a protein now known to protect cancer cells from death messages.

• The firms are betting that giving patients this compound in combination with conventional therapies will kill cancer more effectively. The potential is high, but risk remains—Bcl-2 is unproven as a target, and designing clinical trials for two agents is not straightforward.

• Emerging from a troubled past, Genta initially decided to take the compound to market in the US all on its own. It focused on helping desperately ill patients in small disease indications. Eventually, as encouraging data accumulated, the small firm realized it would be better off partnering.

• The focused indications that Genta chose, and the way it pursued them, made strategic sense for it—but Aventis aspires to develop the drug against major cancer cancers. The large firm can afford to think bigger: it has more money and resources and the benefit of coming in after Genta laid the groundwork.

• Both companies are being guided by theories and observations, fully aware that such things mean little to regulators who demand clinical evidence.

Early in 2002, biotech and pharmaceutical companies were eyeing each other warily, as the industry digested the idea that the $2 billion deal Bristol-Myers Squibb Co. had signed with ImClone Systems Inc. for the cancer drug cetuximab (Erbitux) [See Deal] was going up in smoke and possibly mirrors. The size of that deal had shaken everyone up, and its rapid implosion continued sending out shock waves, increasing the tension of licensing negotiations by reminding everyone that late-phase drug candidates are still risky—especially if they're against novel targets. Then in April, Genta Inc. announced some news that both big and small companies could find encouraging.

Genta licensed to Aventis SA worldwide rights to its lead drug candidate, an antisense inhibitor of a protein called Bcl-2, which has been shown to be a participant in the cellular process known as apoptosis, alias programmed cell death [See Deal]. The companies believe that by blocking this factor, the compound will act as a sort of chemosensitizer or potentiator that will help approved cancer drugs work better. The deal included an upfront payment of $137 million, of which nearly $72 million reflected purchase of Genta equity. If all goes well, this will be followed by a series of approval-linked milestones that could bring Genta roughly $480 million in cash, equity, milestones and convertible debt. Aventis agreed to fund 75% of NDA-directed clinical trial costs going forward, and will also pay for the biotech firm to establish a small sales force that will co-market the product in the US. Genta will also collect royalties on all worldwide sales, and both companies' names will feature with equal prominence in promotions.

The licensing deal—the second largest ever for a single late-phase biotech drug, after ImClone and BMS's agreement on Erbitux—was inspiring because it showed that Big Pharma companies were still willing to pay biotech firms good money for promising drug candidates, and that both sides could be reasonable. Genta won't collect huge sums before proving its product works, but it will be rewarded if the drug gets to market quickly, then continues to win approvals for new indications. After the initial upfront payment, all the monies in this deal are connected to milestones that matter—actual marketing approvals.

With the deal announcement, suddenly, Genta was in the spotlight and looking good. That wasn't always the case. The company founded in 1988 to commercialize antisense technology spent years working on basic scientific issues, and amassed about 100 patents claiming use of antisense to treat conditions as diverse as hair loss and Alzheimer's disease. The firm attended lots of scientific conferences, but never any clinical ones. Genta didn't settle on a therapeutic focus until 1995, when it took Genasense—at the time known only as G3139—into clinical trials in the United Kingdom as a single-agent treatment for non-Hodgkin's lymphoma (NHL), a cancer of B cells known to express high quantities of Bcl-2. (The protein gets its name from B cell lymphoma, where it was first identified.)

In 1996, Genta was vastly overextended. Hours from bankruptcy, the company was refinanced by Paramount Capital, which in 1997 brought in Kenneth Kasses, formerly president of the radiopharmaceutical division of the DuPont Merck Pharmaceutical Co., (now a Bristol-Myers Squibb division), as an interim CEO to stabilize the patient. Kasses sold off Genta assets including a manufacturing plant, restructured programs and laid off staff until just four employees remained. He closed the offices in La Jolla, CA and moved the company East, but allowed the clinical trial begun by the company's founders to carry on.

When Raymond Warrell, Jr., MD, became Genta's new CEO in December 1999, he knew he was taking on a big challenge. Warrell had earned an excellent reputation as a clinical oncologist and attained a powerful position in that field of medicine, serving as associate physician-in-chief and tenured member of Memorial Sloan-Kettering Cancer Center. He'd been a professor of medicine at Cornell University and had also gotten an MBA at Columbia University. His business training and clinical expertise stood him well in consulting for companies—including a short stint for Genta, although his advise wasn't followed. He'd co-founded two companies, and helped develop arsenic trioxide as a cancer treatment.

Warrell was an accomplished man, but he had never been in charge of running a biotech company—and Genta was still in decidedly rough shape. Warrell had to bring it back to health, working with the anti-cancer compound that was the company's best remaining asset. One of the key things Warrell did was give this molecule a proper name: G3139 was dubbed oblimersen, alias Genasense. Warrell began shifting Genta's focus away from technology toward product, off of antisense and onto a mechanism of action that was growing steadily more intriguing.

Warrell says he and Genta are the lucky beneficiaries of a decade of international scientific studies. Starting in the early 1990s, a growing pile of publications by academic investigators around the world began to suggest that Bcl-2 was playing an important role in cell survival. In 1995, when Genta initiated clinical studies of antisense designed to bind Bcl-2, there was only modest recognition of the protein's role. But about that time, apoptosis became a hot research field and soon a whole family of Bcl proteins that could prevent cell death were identified as actors in cell survival and cell proliferation pathways.

By the time Warrell stepped into the top spot at Genta, the mounting scientific evidence was complemented by reports from academics who'd asked to test Genasense. Their studies were showing that the compound seemed to help patients By then, researchers were also reasonably certain that chemical modifications meant to stabilize the antisense molecules did not have inherent toxicities. Genasense seemed unlikely to harm normal cells and potentially able to treat a broad range of cancers.

The increased scientific understanding of Bcl-2 and data specific to Genasense prompted Warrell to rethink the clinical trial he'd inherited. He decided the compound was more likely to have its best effects not as a single agent, but by helping other therapies work better. He decided that Genta could make use of the toxicology and dosing data generated thus far, but that it definitely needed a different clinical plan. He decided to test Genasense in combination with other drugs in desperately ill cancer patients where treatment options were poor, so that the compound might qualify for Fast Track review.

Instead of betting everything on one indication where Bcl-2 seemed likely to be a good target, Warrell decided to spread the chips and the risks over three indications that made clinical and commercial sense: malignant melanoma, multiple myeloma and chronic lymphocytic leukemia (CLL). Developing Genasense for these diseases, as a potentiator of approved agents, was appealing for several reasons: the science suggested that the compound would perform better in combination than alone, and the market risk was lower heading for new areas with poor treatment options than it would have been following in the big bootprints of Idec Pharmaceuticals Corp. 's rituximab (Rituxan), which won approval in November 1997 for NHL.

Genta's financial risk dropped too, because management knew that FDA would be likely to accept data from fewer patients in the new indications than if the firm persisted in trying to develop another new therapy for NHL, where Rituxan was working well. For a company that ended 1999 with just $10 million in cash, being mindful of such matters was vital. The revised strategy increased investors' confidence in the company: by the end of 2000, two equity placements had brought Genta another $43 million to carry out the registration trials [See Deal] [See Deal]. (It subsequently added another $32.7 million in 2001 via the same route [See Deal].)

Genta needed only one of the three trials to succeed, to win marketing approval and begin selling Genasense into a reasonable-sized niche occupied by needy patients. If one or both of the other trials turned out well, the company would be that much better off. The triple-play was also potentially protective in another way: since the trials all started around the same time, Genta's managers knew that if the first study failed, they could tell the market to wait for the next, and hopefully keep the stock from dipping as badly as it would if the firm had only one prospect. (The company, earlier dropped from Nasdaq's main trading board regained its listing there at the start of May 2000.)

c: Although Warrell was determined to see that the three new trials of Genasense were approval-bound, he didn't want to waste the CRADA grant from the National Institutes of Health 's National Cancer Institute (NCI) Genta had won in 1998. He reasoned that having a network of NCI researchers studying the drug could be a unique source of leverage. Genta hadn't managed those relationships well in the past, Warrell says, explaining it was "a question of expectations." Warrell, with his many years as a clinical oncologist, realized that the interests of academic researchers are not allied with those of any company. They're not interested in commercial goals; they're not so motivated by deadlines. So he played to their strengths—encouraging academic investigators to pursue clinical and scientific questions that would be of help to Genta, but not expecting program investigators to run studies on the critical path for registration.

Novelty Brings Risk, But It's Manageable

Warrell downplays the risks that Genta faced then and now, yet a tiny company with a reasoned clinical plan but not a lot of cash, developing a compound against an unproven target, is ipso facto bearing a lot of risk. No matter how good the theory behind a drug's mechanism, novel targets pump up technology risk. Clinical and financial risks spike up in definable ways too. How does a company develop a compound it believes interacts with a novel mechanism, in a way that ups its chances of winning regulatory approval as quickly and inexpensively as possible? Which diseases should a company with high hopes and modest means shoot for, first?

Big companies confront the same risks as small ones when developing a compound against a novel target, but they do so on a different plane—even when they're intent on the very same molecule. The new partnership between Genta and Aventis illustrates these differences in perspective and potential. The story has two halves—first, the story of how the initial development work on Genasense led up to negotiations and a deal with this particular suitor, and second, the still-unfolding tale of how Aventis aims to maximize the value of the compound.

Both firms' development plans have been and continue to be driven on by theories of mechanism and measurements of markers that their scientists find compelling. But the companies acknowledge that these inspirations and observations are unlikely to sway the FDA. Regulators may have an interest in science, but they require clinical evidence. In this case, since the trials are based on drug combinations, just showing a tumor response won't do. Recognizing that reality, Genta and Aventis, while reaching for very different markets, both say they need to prove beyond doubt that adding Genasense to a standard therapy improves patients' survival or time to disease progression.

Bcl-2 as Gatekeeper

Genta managers describe Bcl-2 as a cell-protection factor that lets cancer cells resist death messages sent by the body's own defense system and by treatments such as chemotherapy, radiation or immunotherapy. Loretta Itri, MD, FACP, Genta's EVP, clinical research and development [and Ray Warrell's wife] explains that normally, when a cancer cell comes under attack, mitochondria within the cell receive the death signal and release a substance called cytochrome C, which activates enzymes known as caspases. These enzymes chop up cell proteins, and the fragmentation leads to cell death. The caspase cascade is tremendously powerful, she declares: "If you trigger it, it's irreversible. In six hours, cells are committed to die." Itri explains that Bcl-2 sits in the mitochondrial membrane, where it blocks release of cytochrome C and so prevents the caspases from being activated. This gives the cell a survival advantage.

"Taking away this gatekeeper," asserts Bruce Williams, Genta's SVP, sales and marketing, "should make cancer cells more vulnerable to attack." Genta is betting that Genasense will remove the protection Bcl-2 provides, and so allow the normal biological process of apoptosis to proceed. The company believes the protein contributes to both inherent and acquired resistance to current anticancer treatments—in that some Bcl-2 is present in most cancer cells and more is produced as they come under attack.

Williams notes that growing understanding of the apoptotic pathway, in which Bcl-2 appears to play a vital role, is changing the way researchers and clinicians think about cancer. It wasn't long ago that medical schools taught that cancer was a hyperproliferative disorder, a case of essentially normal cells growing wildly out of control. Molecular biologists have been steadily unveiling some of the substances and signals that spark cell growth, but they have also been uncovering evidence that suggests cancer results when cells fail to die. It's now known that cells receive and process messages to grow and to die through many pathways; the abundance of alternate routes seems to be a key means by which cancer cells evade death messages and become resistant to treatment.

Genta and now Aventis are betting that Genasense influences a biological pathway so fundamental that just about every kind of cancer treatment should get a boost from co-treatment with this compound. In some of the study designs, the protocol calls for giving patients a dose of a cytotoxic agent (to stimulate Bcl-2), then infusing patients with Genasense daily for six days (to take away the factor and weaken the cells), then giving another dose of the toxic agent. This regimen may be repeated a number of times, spaced by several weeks. Warrell says that when he began analyzing the data that Genta had accumulated, there were "tantalizing hints of activity in many areas from studies that his predecessor had gotten underway with NCI researchers, through the CRADA. But the small company couldn't afford to follow all the leads.

Setting up the Trials

Loretta Itri says that Genta is probably not going to try to identify a patient population where Genasense would have effect as a single agent—but neither, she argues, are most other firms developing novel compounds meant to interfere with molecular factors that are just part of the big picture of how cancers grow and maintain themselves. Conventional chemotherapeutics are poisons primed to kill rapidly dividing cells, but they don't just kill cancer cells. They also take out normal cells, and that's what causes nausea and hair loss. Proving efficacy is generally less of a problem than demonstrating that their toxicity is bearable within a manageable therapeutic window—in other words, before too much damage occurs to normal cells. New agents like Genasense that are intended to interfere with apoptosis, cell survival or cell proliferation will probably have the opposite problem. Because they are designed to hit specific molecular targets, the new agents are turning out to be relatively gentle on the rest of a patient's body.

Because most of the new, targeted agents probably won't be strong enough to kill cancer by themselves, their effects can't be measured in conventional ways. Consider: typically, Phase I trials of a drug test its safety, then Phase II trials test its efficacy in a specific patient population by some measure, such as tumor shrinkage (response rate), before Phase III trials go on to confirm that this measurable effect actually does provide a significant clinical benefit such as helping the patient live longer, or extending the amount of time before cancer progresses. But if a drug does not—cannot—shrink a tumor on its own, but instead makes a tumor more vulnerable to attack by standard therapy, demonstrating that calls for drug combinations, and for something other than standard oncology study design.

Warrell says that testing the drug for use in combination "was no big deal—it just had to be done right." But judging from the number of recent stumbles by drug developers who've tested their novel, molecularly targeted agents in combination with approved cancer therapies, the challenge may not be as straightforward as he maintains. Pharmacia Corp. 's Sugen Inc. subsidiary halted the Phase III trial of its angiogenesis inhibitor semaxinib, which it had hoped would make standard chemotherapy more effective against colorectal cancer. AstraZeneca PLC 's gefitinib (Iressa) failed to increase benefits to patients with small-cell lung cancer when tested in combination with conventional platinum-based agents. (See "Testing Drugs Against New Targets: Like Playing Blind Man's Bluff?" IN VIVO, October 2002 (Also see "Testing Drugs Against New Targets: Like Playing Blind Man's Bluff?" - In Vivo, 1 Oct, 2002.).) Early this year Genentech Inc. 's Phase III trial of bevacizumab (Avastin) in combination with capecitabine (Xeloda) against metastatic breast cancer failed to meet its primary efficacy endpoint.

At the end of last year, the FDA declined to even review the biologics licensing application that ImClone hoped would win approval for Erbitux, as a treatment with the drug irinotecan for colorectal cancer in patients refractory (resistant) to treatment with that agent. Regulators called the company to task for, among other things, failing to prove beyond doubt that the patients taken into its trial actually were refractory to the drug they had been given and which they continued to receive in addition to Erbitux. That made it difficult if not impossible for reviewers to tell what contribution the new drug made. ImClone also drew criticism for failing to include a control arm in its study, which would have given regulators a rigorous comparison of the combination's effects versus standard therapy.

Companies commonly "take missteps" in other ways too, observes Michael Vasconcelles, MD, senior medical director at Genzyme Molecular Oncology , a Genzyme Corp. division. He notes, for instance, that underpowered studies (those that fail to show statistically significant benefit due to insufficient numbers of patients or follow-up) can miss positive results. "It's been shown time and time and time again," he says, adding that cost issues often prevent companies from doing multiple studies that might turn up small but real, approval-worthy clinical benefits. Vasconcelles also cites patient selection as a typical problem area: Did the data that led to the study define the population the drug developer should be looking at, and testing the drug in? "Sometimes you have to make decisions about trial design without the best information," he explains. "If the outcome is negative, it doesn't necessarily mean the drug is bad—it just means the company didn't have enough information at the time they started the trial [to power it appropriately]."

Biotech companies may slip up more often than major drugmakers, if only because they are under greater time and financial pressure than Big Pharma companies, observes Bruce Williams. He notes that sometimes biotechs try to prove to the Street that they're more nimble than big companies. Or they feel they need to quickly move things into trials so they can get to market faster and justify their valuations. "Many come under pressure from their boards and their backers, to do a $10 million study for $3 million," Williams points out.

The pressures of designing and running clinical trials are real, but Warrell emphasizes, "Cutting corners never saves time. You end up having to re-do things, and that only hurts you and your investors." He speaks not only as an observer of the industry, but from personal experience with Genta.

Picking Commercial Indications

It didn't take Warrell long to conclude that the clinical trials Genta was running when he arrived were "going nowhere." From his perspective, the most advanced trial against NHL—underway for five years by then—shared an important flaw with several other Genasense trials being carried out by NCI researchers. Researchers at the University of Vienna had also showed striking results when testing the drug in combination with chemotherapy against malignant melanoma. But none of these trials were randomized, meaning that clinicians were not separating equal numbers of like patients into treatment versus control arms. That was perfectly reasonable from an academic and clinical perspective; doctors were hoping that a novel therapy could help their patients. But from a regulator's standpoint, it would be hard to establish a lack of physician bias in favor of Genasense.

By dint of their structure, the trials underway when Warrell came into the company would not ever yield information that Genta could submit to FDA to prove efficacy, he asserts. "You could spend years doing studies like that, but never get the data you need to be on a regulatory path," Warrell says. He believed the drug had been in humans plenty long enough to establish its safety.

It was time to get on with it. Warrell called a halt to many of the non-randomized trials, and the decision did ruffle some feathers at NCI. But the clinician-turned-executive explained that Genta simply couldn't afford to continue supplying an expensive drug for studies that weren't going to bring Genasense closer to approval.

Some basic scientific work on Bcl-2 done outside of Genta helped Warrell select clinical indications he thought did make commercial sense for the company. He explains that a knock-out mouse engineered to lack the gene for Bcl-2 had fur that was almost completely white, because the melanocytes that give rise to pigment had undergone apoptosis. The mouse also had practically no lymphoid tissue. "The rest of him was completely normal, so knocking out this gene in general isn't going to have much effect," Warrell declares. The findings encouraged Genta to consider life-threatening cancers other than NHL involving lymphocytes and melanocytes.

Warrell decided to test Genasense against CLL and myeloma because these so-called "liquid tumors" circulate through the blood stream rather than forming a bulky tumor, and so might be more readily accessible. NHL is also a lymphocytic liquid tumor, and although those diseases never had the prime market appeal of solid tumors like lung and breast, the success of Rituxan was proving otherwise.

He also chose malignant melanoma, a virulent type of skin cancer, based on the promising but non-randomized trial at the University of Vienna. "People who should have been dead were walking around," Warrell declares. It was reasonable to think the stuff was working—the observation jived with investigators' observation that Bcl-2 was upregulated in that disease—and to see if those results would bear out in a randomized trial.

"You bet Genta chose those indications carefully," says Bruce Williams, who joined Genta as SVP, sales and marketing in early 2001 when the company had just 22 employees. The indications made sense for a small company on a tight budget because current therapies are ineffective; any added benefit would be a huge step forward. "In that kind of environment, regulatory hurdles are lower," he says. And though he doesn't mention it, with Rituxan out there, NHL was less appealing. "These are also diseases in which you can get meaningful data quickly," Williams notes. Sadly, the expected survival period for patients with Stage 4 melanoma is just six months. If administering Genasense in combination with dacarbazine can allow patients to live three months longer, then the drug combination will have improved survival by 50%.

For Warrell, the drive to get on with it meant that Genta should put Genasense directly into a pivotal trial. Call it Phase II or Phase III or Phase II/III, the point was that it be randomized and capable of producing the data FDA requires for a drug approval.

Warrell felt taking Genasense into pivotal trials was the right thing to do, at least partly because he knew that other cancer drugs had won FDA approval on the basis of relatively small pivotal Phase II trials. Idec's Rituxan was one, and Warrell himself had helped develop arsenic trioxide (Trisenox) as a treatment for acute promylocytic leukemia at PolaRx Biopharmaceuticals Inc. , a company he co-founded that was later sold to Cell Therapeutics Inc. [See Deal]. In that indication, just 50 patients were pivotal for approval. Other companies have since had success with that strategy. Wyeth got gemtuzumab ozogamicin (Mylotarg) approved on Phase II data with no control studies. Millennium Pharmaceuticals Inc. and Ilex Oncology Inc. did the same with alemtuzumab (Campath). Novartis AG won rapid approval for imatinib mesylate (Gleevec) as a treatment for chronic myeloid leukemia on the basis of Phase II data.

Those cancer drugs were all approved as single agents, not as combination therapies—but Warrell insists the point simply is not pertinent. "The regulators didn't scratch their heads with leucovorin or Neupogen," he says. Those compounds were approved for use in cancer patients receiving other therapies, although again, the comparisons are not precise. Leucovorin is a vitamin, the active form of the B vitamin folic acid, which is given to protect normal cells from drugs like methotrexate that deplete folic acid. Amgen Inc. 's filgrastim (Neupogen) is a recombinant form of the human protein granulocyte colony-stimulating factor (G-CSF). So both are arguably restorative therapy, given to offset damage done by chemotherapy.

Warrell is confident that FDA regulators will have absolutely no reason to balk when Genta asks that Genasense be approved in combination with other drugs, rather than a single agent. "We'll have much more data than Millennium and Ilex presented in CLL," he declares, adding that, "Everything is context. These are well-designed trials. These should be no-brainer applications, easy for anyone to approve."

Warrell's confidence aside, some industry observers do believe that structuring a clinical trial for a new drug that's meant to be used in combination therapy, but which hasn't been approved as a single agent, presents more than the usual challenge. Among them is Dennis Brown, PhD, founder and CEO of ChemGenex Therapeutics Inc. and co-founder of Matrix Pharmaceutical Inc. (now a division of Chiron Corp. ), who has 25 years of experience in basic and applied cancer research and over 15 years experience with developing products. He explains that "You're bringing a compound whose activity can't be identified on its own, and asking FDA to regulate that.When you're testing A versus A+B, the FDA wants to know a lot about B," he declares. Dosing levels can raise questions at the agency, as can the approved agent that a company selects, Brown says. He notes that dacarbazine is an approved drug for treatment of melanoma, but that "it's seldom used in clinical practice any more, as people have moved on to platinum-based therapies like cisplatin." So what made that the right choice for testing in combination with Genasense, if the drug is barely used any more?

Loretta Itri points out that clinicians use many drugs to treat melanoma—that's the crux of oncology care, that people pit all kinds of compounds against tumors, trying to mix and match different mechanisms. In the case of melanoma, dacarbazine is the only drug specifically approved by FDA for treatment, she says. "Do I think it's a good treatment? No, but I'd argue there's nothing better."

In Genta's trial against multiple myeloma, the company is looking at time to disease progression, "because that's what the agency wanted," Itri declares. "We went down with a slightly different protocol, but dexamethazone plus Genasense is what they approved. We were granted expedited review, because it's appropriate. For patients with advanced disease, for whom no other therapy is effective, the agency is pretty reasonable."

Preparing to Partner

Warrell says that Genta did not pay much attention to the ways other companies went about developing combination therapies, when it set to re-designing the clinical development strategy for Genasense. It seems he decided that the best way for Genta to manage the risk introduced by the novelty of Bcl-2, and the novelty of antisense, was to be conservative in all other regards—to do right those things the company could do right. "I'm a very conventional, old-timey oncology drug developer. I don't buy into new paradigms, or follow the line that ‘you have to develop stuff in new ways because we're breaking old molds,'" he declares, adding, "This is a conventional development path, and that's the key to the success of the program. We're not invoking new paradigms." Conventional, perhaps, but some would say more difficult because of the combination setting.

Genta's focus on small but respectable patient populations reflects the firm's original intention to take Genasense from clinic to market, on its own in the US. But as the trials advanced and the study of apoptosis heated up, increasing understanding of the Bcl family of proteins and their role in preventing cell death, the small company grew more confident about the value of its drug candidate.

Warrell determined that the company needed to start making some noise about Genasense, where doing so would do it some good. Genta hadn't done much to get attention for the drug candidate before he arrived. The company had presented about its antisense technology at many scientific and technical conferences, but until 2000 had never been to ASCO, the American Society of Clinical Oncology conference that most firms developing cancer drugs consider an essential place to appear each year.

At the 2001 ASCO meeting, Genta met with 11 potential partners. Warrell hoped one of the largest pharmaceutical companies would license the compound for ex-US development, but the big fish weren't biting. They wanted global rights or nothing. That was okay with Genta managers; they continued talking to other companies, including mid-sized European ones, and nurturing their own plans to commercialize Genasense-.

At about this time, Loretta Itri started to come to the conclusion that no matter how much Warrell raised in cash, it wouldn't do justice the compound. "I've developed drugs for Big Pharma companies. I know what it takes," she declares. To maximize the value of Genasense, the company was going to need a partner.

Then came the ImClone deal with Bristol-Myers in September 2001, and the spectacular deal terms immediately inspired Genta to reconsider its marketing plan. If BMS was willing to purchase $1 billion worth of equity and pay $200 million at signing to get Erbitux, then pay another $300 million upon FDA acceptance of the submission filing, another $500 million upon approval and hand over 39% of net sales for 17 years, all for a product whose European rights had already been signed away (to Merck KGAA [See Deal])—well, it was time to reconsider the plan. Genta execs didn't think that Erbitux had nearly the market potential of Genasense. And it was one of just several anti-cancer compounds (including Iressa) that are heading to market, for use in combination with approved drugs.

Genta figured that it ought to be able to do a big deal too. Genasense was a Phase III product directed to a target with a strong biological rationale. The cloud that had been hanging around the compound because it was an antisense molecule rather than a conventional chemical was rapidly dissipating, thanks to an August 2001 deal between Isis Pharmaceuticals Inc. and Eli Lilly & Co. for an inhibitor of protein kinase C-alpha expression, then in early Phase III clinical trials against non-small cell lung cancer [See Deal]. No antisense-based therapeutic had made it to market yet, but here was a respected company taking a chance on one, and accessing technology rights too.

The ImClone deal, the broken antisense hex, and a growing industry trend towards testing novel anti-cancer agents in combination trials, pre-approval, all these factors began shifting Genta's estimation of the sort of deal it might negotiate for itself. "We immediately added a zero to our asking price for Genasense," Warrell says, and then the company began sketching various visions of what it would bring to, and expect from, a partner.

"Once we calculated that this was not going to be a niche $300 million product, there was no scenario under which Genta didn't come out better with a partner," Bruce Williams declares. Genta called back the major drugmakers who'd walked away when the firm was still intent on keeping the US for itself, to see if they'd be interested in worldwide rights. Aventis was one of those that came back to the table. But the ImClone deal had done more than embolden Genta; it had also set Big Pharma licensing executives on the defensive. Williams recalls, "Lots of people told us, ‘If you think we're going to do a deal that makes us lose money, think again.' People understood that BMS did that deal at that value to protect its oncology franchise. They said, ‘They're desperate. We're not.'"

Williams says now that Genta felt fairly sure it would partner with Aventis, but kept another potential partner on the string just in case, letting go just weeks before the deal was finalized. Aventis's expertise was part of the appeal for Genta. "They're God's gift to solid tumors," Warrell says – the firm markets docetaxel (Taxotere), among other things, and therefore, he believes, provides a good complement to the strengths that Genta's people have in hematological cancers. Genta also liked the depth of scientific resources Aventis could bring to bear in oncology.

But Genta was especially impressed with Aventis's aspirations for Genasense—the larger firm thought the drug could be big, and was prepared to quickly get into development work that other firms weren't mentioning, or wouldn't consider commencing for several years. "You can be laissez-faire about market acceptance, or you can accelerate it by setting up or encouraging studies," Williams says, adding, "From the day we started talking seriously, it was clear that Aventis had as big or bigger expectations than we did, and an as-great or greater sense of urgency. We didn't see that from others."

Aventis was mindful of competition when it took an aggressive approach to building the market for Taxotere, Williams explains. Years before BMS lost patent protection on paclitaxel (Taxol), "their strategy was to get Taxotere associated with new therapies," so that when clinicians thought about giving patients drugs in combination, they'd think of using Taxotere, not Taxol. Genasense was one of those emerging therapeutics, and it likewise made sense for Genta to lock onto a big, accepted cancer drug.

Williams says he still can't figure why other companies weren't thinking that way. Some used a valuation model based on nothing more than the late-phase trials Genta had initiated. "Maybe they were trying to lower our expectations," he muses, but eventually, that stance pushed Genta away.

For its part, Aventis liked the theory behind Bcl-2 as a target, the idea that this protein is one of, if not the most prominent escape routes by which cancer cells avoid death. And the big company was satisfied with the data Genta had accumulated. "We would've loved it, if they'd had a greater volume of clinical data," but what they had was solid, says Bruce Seeley, Aventis's head of new product commercialization and licensing for oncology, and also manager of the alliance with Genta. "You'd better believe that in the wake of ImClone's mess with Bristol-Myers, we were extra careful about our due diligence," he says. The academic literature was also positive about Bcl-2's role in apoptosis. Even though no currently marketed drug hits that target, Seeley believes, "It's a strong biological rationale."

Aventis didn't have to settle for just theory, or Genta's documentation, however: back when the biotech company was looking for an ex-US deal only, it had given Aventis some of the compound to experiment with in its own labs. This turned out to be a key factor in the deal, Seeley says, explaining how an Aventis research group outside of Paris had tested Genasense in the tumor models earlier used to develop Taxotere.

"We tested Genasense in cells resistant to Taxotere, cells responsive to it, and cells we knew to be partially responsive to it, and it was fantastic. It was better than Taxotere itself," Seeley declares. He suggests that the Aventis group that tested Genasense, and gave its stamp of approval, was apparently already well aware of the protein's potential. He says the deal got done because, "we wanted to get at the target, Bcl-2, and this was the fastest way of doing so, since it was already in Phase III."

Aventis's Appetite for Risk

Despite the strong experimental evidence Aventis scientists generated in their own labs, the alliance is nevertheless structured in a way that limits the Big Pharma company's risk. Ray Warrell bristles at the very suggestion, emphasizing that a company as big as Aventis wouldn't have signed such a rich deal—and paid $137 million upfront—if it thought the compound was risky.

But while there was some upfront money, the bulk of the deal value is hitched to approval milestones—not to clinical or submission milestones, points out Thomas Hofstaetter, SVP, business development for Aventis. "Genta will get a lot of money, but only if the drug is approved and only if they add five or six additional indications," he explains. With the first approval of Genasense in the US (presumably for myeloma, melanoma or CLL), Genta stands to collect $75 million in cash plus a $20 million allotment of convertible debt. Genta will get $40 million for the second US approval, and $20 million each for the first and second European approvals. About a third of the total deal value is tied to approvals for "major" cancers, such as those of the prostate, breast, colon or lung: Genta is promised $40 million for the first such major US approval; $40 million for the first front-line major US approval, and $45 million for the second major US approval.

"Our key interest in the compound is in using it in combination with other drugs to treat large solid tumors, such as those in the breast and lung, and our expectations are based on our own experiments," Hofstaetter asserts. He notes that although Genasense has been tested in large tumors in "some of the usual Phase I/II trials" by NCI researchers and some Europeans, these are not registration trials. The sorts of clinical trials Aventis is looking for are only just getting underway in such diseases. "It would be beautiful if one of the current three trials leads to an approval, because that would bring the drug to market, allow people in the clinic to develop their own models, get some revenues coming in and prove the principle. That's what we hope for, but the odds are high," Hofstaetter says. There's no doubt that it works, he asserts, "But as the Erbitux and Iressa trials show, it's not necessarily straightforward when you use two agents. This is a new era of research, and we have to figure out how it's done."

Testing Genasense in the indications Genta chose, the way it did, was "sound strategy from their point of view, but I don't think even Genta expects all three trials to succeed," Hofstaetter observes. As for Aventis, he says, "We don't expect the results to be negative, but it may be they don't quite reach efficacy. It may be that when the results are in, we'll have to do another trial."

As Aventis sees it, part of the risk stems from Genta's decision to rely on just one pivotal trial in each indication. Hofstaetter says he understands that the small company couldn't afford to do more that that, but explains why the approach could be a problem. Normally, if a company shows FDA that a drug produces a survival benefit of 5% compared to standard treatment, the agency will grant approval if that result can be proved in a second trial. Without that second trial, "it could be just a freak result, something biased in favor of a treatment group," he notes. Hofstaetter says that companies seeking approval based on a single trial have to show a much higher statistical difference—the hurdle is on the order of twenty percent. "But twenty percent is awfully high. By doing a single trial with a minimum number of patients, you're cutting things very close. We would do two trials to be on the safe side," he says.

Aventis would also have preferred if Genta did larger trials—and it told its partner as much. Adding patients helps protect against the possibility that one or a few outliers will skew the data. "It's not as if we were unaware of the issue. We just couldn't afford to do more," Loretta Itri points out. She notes that even before Aventis came along, her company had already enlarged the study once from 280 to 450 patients. Doing so was advisable, she explains, because in some patients the cancer has invaded the lung, in others it's confined to the skin and lymph nodes. After the deal was finalized, Genta announced that it was expanding its malignant melanoma trial to 750 patients. It wasn't just the money, but resources including contacts in Europe that helped with the expansion.

Aventis need not take the clinical risks that Genta, operating on a limited budget, had to. A major pharmaceutical company simply does not experience the same kind of pressure as a small, no longer young, biotech company that has yet to develop a marketable product and give investors a return. It has more money and time to spend on trials. So, for instance, Aventis does plan to run Phase II trials of Genasense in combination with other drugs, and to use surrogate markers at that phase of development.

"In this age of new compounds, companies question the need to do Phase II trials whose endpoint is response rates, since the agents can't be measured that way. But you can still do some, to show whether or not something is having clinical effect," Bruce Seeley says. He notes that Aventis plans to measure PSA levels when developing combination therapy for prostate cancer, because even though current tests give many false positives and negatives, patients with tumors do have PSA levels that correspond with tumor size. The Big Pharma company figures monitoring those levels in Phase II will help it come up with an optimized dosage that can then proceed to Phase III for survival.

To some extent, the existence of accepted treatment regimens for major cancers gives an edge to would-be developers of combination therapies. In breast cancer, for instance, clinicians follow established chemotherapeutic regimens and their results are quite predictable. So it won't be hard for Aventis to give varying amounts of Genasense during Phase II in addition to standard therapy. The company expects to see relatively quickly what if any effect the add-on is having over standard therapy, and be able so optimize dosing, before proceeding to Phase III—or to opt out, if the results aren't encouraging.

There are other benefits particular to new anti-cancer agents like Genasense that target specific molecular mechanisms of cancer. Traditionally, developers of new cancer drugs have started out by testing their compounds in patients with the worst prognosis. They do that not just to save money, but to spare all but the worst-prognosis patients exposure to cytotoxic agents. But compounds that cause only modest side effects can be handled differently, opening the possibility for many kinds of new treatment approaches, Seeley points out. "This drug is not cytotoxic; it has an excellent safety profile and thus the potential to be combined with everything under the sun," he enthuses.

"We're thinking about looking at early-stage disease earlier," Seeley proclaims, adding that government agencies may become willing to look at different measures, and make some changes in what they approve. Perhaps regulators would consider looking at surrogate endpoints, if a drug developer agreed to run an extended Phase IV trial, he muses. The downside of treating disease earlier is that it would take a very long time to do trials. Trying to show a survival advantage in prostate cancer, for example, could take 10-15 years, and the same could be said for other slow-growing cancers.

Bottom line: Genasense's good safety data is sparking creativity in drug developers at Aventis, by enabling them to look at patient populations they wouldn't otherwise. Aventis would never bet solely on early-stage treatment, because that would be too expensive, too far off and plain too risky. But the company won't wait until it's finished developing Genasense for metastatic cancers—as major drugmakers ordinarily do—before testing the compound in early-stage cancers and other patient populations, in combination with approved drugs. Generally combinations don't come until later in a product's life cycle, but with a novel agent that seems quite safe, Seeley figures it's prudent to start development and formulation work early—either in-house, or through collaborations.

Whereas Genta managed its risks by counting pennies and concentrating on just three diseases with small, needy patient populations, Aventis has to do nearly the opposite to maximize the value of Genasense. Sparing dollars and working with minimum numbers of patients would undercut the big company's chances. If this antisense compound is as powerful but gentle as the theory behind it suggests, then it behooves Aventis to work quickly to get approvals—and at least begin documenting efficacy—in as many big indications as possible.

Aventis knows through its own experience developing Taxotere, and from reflecting on how Genta's path had to change once Rituxan was approved, that new agents can quickly shift market dynamics. If a product can be shown beyond doubt to help patients with a certain disease, then that's what clinicians want to use—and that raises the bar for everyone else developing treatments. Genta and Aventis are not the only companies betting that combination therapies will have a big impact on clinical oncology practice. Others companies are thinking the same sorts of thoughts about molecular targets. Some have stumbled on the way to market, but many will get up and get back on the path, and others coming along behind them will learn from watching.

Aventis is pulling into position to be a front-runner in combination therapy for cancer, but it only got there because Genta bore the early risk of developing Genasense when it was the kind of compound no Big Pharma would have considered. Now that time has passed, and medical biology has advanced in a way that makes Bcl-2 appear to be a very important target, and antisense a viable technology for creating a drug candidate, Aventis can't afford to hang back. The company's executives realize this, and that's why they say they're working with Genta to design protocols for clinical trials against major cancers, so these can get underway as soon as possible. Aventis is also already contemplating what next-generation versions of Genasense might look like, and how the compound could be made even less toxic and more effective. The partners are being guided by theories and observations, knowing that the challenge of treating cancer may begin with science but the battleground swiftly moves to patients' bodies, and the marketplace—that is, if regulators give thumbs up.