In what is rapidly becoming a hallmark of biotech drug development, one basic mechanism of action can be used to treat numerous conditions.
Abstract
This year’s ASCO meeting was, in essence, a showcase for multitargeted therapeutics – those with similar makeup but many potential uses. In what is rapidly becoming a hallmark of biotech drug development, the idea that a basic mechanism of action can be applied to disparate diseases has the potential to move biotechnology forward to better therapies and a more efficient R&D process.
It was a moment to savor. In just weeks, Genentech’s research scientists had delivered hard clinical data that bevacizumab (Avastin) in combination with chemotherapy extended survival in patients with lung, breast, and colon cancers. And, at this summer’s Orlando meeting of the American Society of Clinical Oncology (ASCO), Genentech was heralded for its unprecedented run of clinical triumphs.
“It was the most fun five weeks I might ever have in my career,” Susan Desmond-Hellmann, MD, MPH, Genentech’s president of product development, told Forbes. “It’s what you live for.”
Years of painstaking clinical investigation led to Genentech’s celebratory moment, but this sudden string of trial triumphs also helped to highlight the work of a multitude of scientists who have patiently beavered away at developing single agents that promise multiple uses.
According to several of the scientists involved in special sessions at ASCO, bevacizumab and erlotinib (Tarceva) represent the leading edge of a new class of multitargeted drugs — those with similar makeup but many potential uses. Much work remains, they note, in finding the right dosages and determining which sets of patients are likely to respond to such drugs. But a better understanding of who resists the effects of these drugs could ultimately lead to the development of better therapies.
“It’s an interesting concept, to target multiple pathways,” says Roy Herbst, MD, PhD, chief of the section of thoracic oncology at Houston’s MD Anderson Cancer Center. “Most people feel that’s going to be the wave of the future.”
PHOTOGRAPH BY KOLANOWSKI STUDIO
SINGLE MECHANISM
“It’s an interesting concept, to target multiple pathways,” says Roy Herbst, MD, PhD, chief of the section of thoracic oncology at Houston’s MD Anderson Cancer Center, who participated in the ASCO session on multiple-use drugs. “Most people feel that’s going to be the wave of the future. How we do it will depend on the drug we have.”
The media buzz on Genentech aside, researchers at ASCO also focused attention on other drugs earmarked for their ability to attack multiple diseases.
Already in late-stage development is a new class of multikinase inhibitors that block the flow of blood to tumors. This class includes sunitinib (Sutent), which Pfizer hopes will gain U.S. Food and Drug Administration approval for malignant gastrointestinal stromal tumor and metastatic renal cell carcinoma, but could play a broader role (by itself and combined with other therapies) in stopping other solid tumors in breast, lung, prostate, and colorectal cancers. Sorafenib is being researched by scientists at Bayer and Onyx Pharmaceuticals for kidney cancer, while GlaxoSmith-Kline pursues its studies on lapatinib.
Cancer drugs seem particularly suited to work against varied targets — especially when, like the multikinase inhibitors, they target a single mechanism associated with different types of cancer. But a wide number of drugs have been intensely studied for multiple uses outside oncology (see “All Roads Lead to Inflammation,” on page 60). The Cox-2 inhibitor celecoxib (Celebrex), for example, started as a treatment for arthritis and is the subject of several late-stage cancer trials sponsored by the National Cancer Institute (NCI). In a similar vein, Eyetech and Pfizer adapted knowledge of disease pathways to develop pegaptanib sodium (Macugen) for treating age-related macular degeneration. Macugen is an antiangiogenic, blocking excessive growth of blood vessels in the eye. Use of anti-angiogenesis to prevent blindness puts a novel twist on an approach to fighting cancer — cutting the blood supply to a tumor to stop growth.
“All roads lead to inflammation”.
This catchy title of a session, chaired by Centocor’s senior vice president for immunology, at this year’s Biotechnology Industry Organization convention in Philadelphia aptly summarizes the hottest area of study under the “one drug, many uses” idea.
Numerous biotechs, large and small, are focused on inflammation, turning drug development across diseases — arthritis, gastroenterology, asthma, and cancer, to name a few — inside out. This research has the potential for a big payoff; a single antibody that, with a few dosage adjustments or given in combination with other agents, can effectively treat several conditions may have blockbuster written all over it.
Centocor’s infliximab (Remicade) is a prime example of how a drug that inhibits inflammation has been proven to have many uses. Infliximab blocks overproduction of a protein (tumor necrosis factor-α) in the immune system to control the development of inflammation, ultimately reducing symptoms in such disparate conditions as Crohn’s disease, ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis. Smaller biotechs, which often do not have the deep R&D pockets that a company like Centocor might, are latching onto this idea with vigor, too — as seen with Rigel Pharmaceuticals’ research into links between arthritis, asthma, and lupus (page 59).
The effect of inflammation on cardiovascular health is an important area of study. Recently, Millennium Pharmaceuticals initiated a randomized, double-blind, placebo-controlled phase 2 clinical trial of MLN1202 in patients at risk for atherosclerotic cardiovascular disease. This study is part of a broad clinical development program to evaluate the anti-inflammatory effects of MLN1202, a humanized monoclonal antibody, in atherosclerosis, rheumatoid arthritis, multiple sclerosis, and scleroderma.
— Michael D. Dalzell
While science that drives multiple investigations is being proven in the clinic, implications for drug discoverers’ and manufacturers’ business plans haven’t gone unnoticed by investors. More investment capital is flowing to biotech companies that can prove that they’re on track to gain multiple approvals — and access to multiple markets — for a single agent. That, in turn, will keep the focus on other agents that promise to do the same.
AIMING BROADLY
Genentech, of course, is a giant in the biotech field, with some 140 clinical trials underway. Its recent successes have helped to propel its market valuation to the top of the industry, fueling an expansion that has allowed the company to buy new manufacturing facilities and engage in more molecular investigations.
But for smaller biotech companies, the issue of one drug, many uses can be a big concern. When a company has resources to pursue only a handful of drug leads in the pipeline at a time, finding a single agent with the potential to target two or more diseases offers a simple and effective research edge that can have a strong influence on its stock price, its ability to barter better licensing deals, and its long-term revenue potential — just what analysts look at when turning thumbs up or down on a company in a field where marginal failures or successes can affect its fortunes dramatically.
“Everybody thinks about this,” says Donald Payan, MD, executive vice president and chief scientific officer of Rigel Pharmaceuticals. “A niche market is fine, but a broader market is better.”
For a company like Rigel, understanding potential multiple uses is critical to gaining a research edge in the expensive, time-consuming world of new drug development. If a molecule shows solid potential for a new indication, researchers often can bypass preliminary safety studies, shaving years off the research needed to satisfy the FDA relative to a drug’s safety and efficacy. Researchers also gain insights into the ways patients are likely to respond to various dose levels and an understanding of the biomarkers that can identify the most likely responders.
Wall Street also watches with avid interest for news of a drug’s potential for multiple uses.
To gain insight into how Genentech’s bevacizumab compares to other new cancer drugs for multiple uses, ChangeWave Biotech Investor, a weekly newsletter, turned to the physicians whom it routinely polls.
By a wide margin, the group of about 250 that includes cancer specialists — tapped bevacizumab as the most likely drug among the new crop of cancer therapies to gain approval for numerous oncologic uses. Approximately 42 percent of the respondents thought so, placing bevacizumab far ahead of cetuximab (Erbitux), which was named by 12 percent and placed second on the list. Michael Shulman, editor of ChangeWave, says that conclusion reflects an understanding within the profession that because these drugs are so targeted and powerful, they are often less likely than traditional drugs to be considered for off-label uses. “That means the company with the most aggressive trials or epidemiological studies has the best approach.”
“One approach for developing a drug is to observe that a single target or enzyme plays a role in two different disease processes,” says Donald Payan, MD, executive vice president and chief scientific officer of Rigel Pharmaceuticals.
“NATURE IS PARSIMONIOUS”
The market ultimately rewards only those companies that can hit the primary endpoints of a phase 3 trial. The march to phase 3, though, must begin years earlier with a moment of inspiration that’s often based on simple observation.
“One approach for developing a drug is to observe that a single target or enzyme plays a role in two different disease processes,” says Payan. “One target mechanism we’re working on is the cell signaling that occurs when immunoglobulin receptors are engaged by antibodies. When we inhale allergens, antibodies sitting on mast cells in the nose or lungs bind with allergens, and that flips the switch on the receptor,” triggering the body’s allergic response.
“But Mother Nature is parsimonious in the way it uses molecules,” Payan continues. “One of the enzymes active in mast cells also plays a role inside other cells that regulate inflammation. In different circumstances, that enzyme yields different outcomes.” As such, “we can learn from allergy work about [the treatment of] arthritis, and vice versa.”
Rigel’s R406, an oral arthritis molecule, provides an example of how biotechs make this kind of extrapolation.
“If that works for rheumatoid arthritis,” says Payan, “we have data from animal models to suggest it probably will work in certain lupus patients.” The advantage is that when a company starts pursuing a second use for a molecule in development, it can use data from earlier studies — in essence, giving a head start to researchers who understand the potential for side effects or drug interactions, or who have discovered biomarkers that could identify patients more likely to respond to the compound.
“These things help to optimize clinical study designs,” Payan notes. But, he adds, at some point, “it’s important to stop making assumptions and let the data tell you if you’re right or wrong.”
ONE INDICATION LEADS TO ANOTHER
“In the development of lead compounds for cancer prevention, promising agents come from convergence of information from different angles,” says Jaye Viner, MD, MPH, chief of the Gastrointestinal and Other Cancers Research Group at the NCI, which coordinates many trials that are testing agents that might be used for multiple indications. “One set of leads arises from observational data — from population or epidemiologic studies, looking across populations exposed to certain diets or drugs — and noting lower rates of cancer or other conditions,” says Viner. “Such insights could provide leads for future research.”
Leads for multiple uses may arise from, or be confirmed by, preclinical research, animal- or tissue-based studies that demonstrate early signs of efficacy and are worthy of more in-depth studies. Or, researchers might examine whether the major pathway a drug targets may be relevant to other diseases.
Researchers may “be able to tease out the optimal dose, frequency, and duration for administering the drug,” suggests Viner, potentially broadening its impact. That method also may justify a speedier march to phase 3 data — no small matter, considering the amount of time and money it takes to push compounds through definitive efficacy testing.
“Research tends to be iterative,” she says. “Agents approved for one indication can be assessed for other indications, for example, by nesting prevention endpoints within cancer treatment trials or within trials that test candidate agents for non-oncologic indications.”
In the traditional method of drug development, physicians observe how patients react to a drug, gaining insight into other diseases against which it might be used. As researchers and physicians work to adjust ideal doses for patients, that too can lead to new uses.
Methotrexate, for example, began as a therapy in oncology, but researchers later learned that at lower doses it could safely suppress the symptoms of autoimmune diseases such as lupus and rheumatoid arthritis. As new agents come on the market, researchers also have been pushing the envelope of drug efficacy, devising new combination therapies to help patients who were once beyond hope.
In a recent phase 3 trial, for example, researchers reported that cisplatin, a standard chemotherapy treatment, demonstrated a statistically significant response against advanced cervical cancer when combined with another cancer drug, topotecan (Hycamtin). In short, the combination treatment was linked to longer survival rates for a significant group of women in the study who earlier had no effective treatment for their condition.
MD Anderson’s Herbst, as an example, has been involved in clinical research on AMG706, a novel multikinase inhibitor that targets multiple receptors and that is being investigated in midstage trials specifically for thyroid and gastrointestinal stromal tumors.
More recently, researchers have focused on popular new drugs that could eventually offer multiple uses. “Broadly, when you look at non-steroidals or statins, you’re looking at classes that have had phenomenal public health impact with cardiovascular disease and now may help in cancer prevention,” says Viner. “Some are already being tested in combination treatments.”
COX-2 AND CANCER
Sometimes, new drug leads pop up where you don’t expect them.
“With a number of agents, what they were evaluated for wasn’t any great shakes,” says Viner. “But, looking at secondary endpoints, researchers saw interesting effects that prompted additional scrutiny. In phase 2 and 3 trials, you may get a sense as to other conditions that the agents may be effective for. Any information that comes from those ancillary data can’t be considered definitive, but it can justify further investigation.”
Nonetheless, before any data are gathered for analysis, or any clinical trials are designed to test new uses, there has to be that initial scientific insight into a compound’s potential. The NCI launched new studies of celecoxib about six years ago, as the result of the collective vision of several drug developers.
And when researchers found that Cox-2 was overexpressed in cancer tissue, it raised the opportunistic question as to whether inhibiting Cox-2 would prevent cancer.
Scientists also had a mouse model showing that animals testing positive for the Cox-2 gene had more polyps than those without it, suggesting that the gene might play a major role in carcinogenesis. More in-depth studies have helped show that the early connection between Cox-2 expression and cancer applies to several cancer types.
Celecoxib has proved effective at higher doses in reducing adenomatous polyps by 40 percent, says Viner. That can be particularly important for people who suffer from a rare genetic condition characterized by a carpeting of polyps in the colon and a high risk for colorectal cancer. And, while there are no data to prove which polyps will pose a clinical threat, it is reasonable to assume that if a certain number of polyps will evolve to cancer, then reducing the number of polyps reduces that threat.
Researchers at NCI also have been studying how nonsteroidal anti-inflammatory drugs can work when teamed up with other therapies. “Because there is an expanding body of preclinical data that shows nonsteroidals work additively, if not synergistically, with other chemopreventives,” says Viner, “it becomes compelling to test the combinations — sometimes at lower doses than those used in the single agent studies — to see if you can get greater efficacy with a lower risk of side effects.”
SAFETY IS PARAMOUNT
Just as some drugs may work against unexpected disease targets, they sometimes raise unexpected threats. As news of Cox-2’s cardiovascular risks hit the headlines, NCI and other researchers in the field quickly responded. “The safety of patients is paramount,” says Viner. “There had to be assurance that there is no disproportionate risk of serious cardiovascular disease.”
At MD Anderson, researchers suspended a trial designed to determine if celecoxib could prevent lung cancer in smokers, resuming the study only after careful screening of patients for cardiovascular risks and at the urging of the NCI.
While keeping one eye on patients’ blood pressure and lipid counts, researchers at the world-renowned cancer center decided to forge ahead, persuaded that the data were pointing them to potentially significant oncology drug advances.
“Nothing is available to deter lung cancer in smokers, even in those who have quit,” said principal investigator Jonathan M. Kurie, MD, a professor in the department of thoracic/head and neck oncology at MD Anderson, when the trial resumed. “We believe the potential benefit to the patient exceeds the risk, and we have ample safeguards in place. We believe this drug has potential to reduce the lung cancer risk.”
As long as there are unmet medical needs, the quest to develop multiple uses for drugs will play a role in drug development. Among biotechnology companies, for whom R&D expenditures for even a single product have the potential to soar into 10 figures, such a strategy will be a leading tactic. For third-party payers and employer purchasers, who are ultimately affected by the cost of biotech drug development, developments along these lines are especially worth watching.