BUSINESS derstanding each others' science" and working together in the lab. Vical develops vaccines based on a proprietary plasmid D N A technology platform. These plasmid vaccines activate skeletal muscles to manufacture desired proteins and antigens. The company has a melanoma therapy in Phase III clinical trials and a cytomegalovirus treatment for bone marrow transplants in Phase II. It also has an angiogenesis therapy developed RICK MULLIN, C&EN NORTHEAST NEWS BUREAU with AnGes, a Japanese biopharma company, in Phase III trials. to market. This is true especially in partINCE ITS DAWNING IN THE EARnerships with big drug companies. "Gone Moreover, the National Institutes of ly 1980s, the biopharmaceutiare the days when biotech companies partHealth recently announced that it will go cal industry has been characner in Phase I clinical trials for relatively forward with Phase II trials of an HlVvacterized by large, slow-moving low economics and loss of control," Mocine based on Vical technology placing a waves of new technologies nane says. "Partnership agreements now $12 million order with the company to supcoming to market. The first, consisting of show the prowess ofbiotech companies in ply the vaccine for the trials. Vical is also vaccines and recombinant protein theracodevelopment and comarketing." working with N I H on vaccines for SARS pies, was followed by a monoclonal anti(severe acute respiratory syndrome), Ebobody wave, which after 12 years is now the dominant force bringing new biotech MUCH OF the maturity and sophistication la, and West Nile disease, with Phase I trials under way in all three areas. drugs to market. in biotech laboratories has to do with the ascendant role of chemistry Several inPerhaps the company's most important On the horizon, however, there are sevdustry players cite a resurgence of medicrecent milestone, however, is in protecteral crests. The sea, in fact, is becoming inal chemistry as biopharmaceutical coming Canadian farm-raised salmon against rather choppy as the "next wave" in biotech panies develop drug formulations that infectious hematopoietic necrosis virus. shapes up to include a spate of new techguarantee powerful therapies will reach Vical's licensee, Novartis affiliate Aqua nologies ranging from gene therapy and specific targets in the body Health Ltd., last month received approval cell-signaling drugs to new twists on vacfrom the Canadian Food Incines and monoclonal antibodspection Agency to sell APEXies that are moving into adI H N vaccine, developed using vanced clinical trials and onto Vical's D N A technology "It is the market. approved in a food animal, At the BIO 2005 convention which is a breakthrough milein Philadelphia in June, for exstone," Samant says. "It passed a ample, there was a palpable lot of regulatory hurdles, which sense that biotechnology, long makes life easier for anything perceived as falling short on its coming behind it." promise ofbreakthrough drugs, is about to deliver. Companies Vical's plasmid D N A techthat only a few years ago shownology was discovered by accicased promising new drug disdent, Samant says. In the 1980s, covery platforms, and little else, the company was developing a now have their first candidates technique for reducing drug side in clinical trials. While few ineffects by delivering drug predustry watchers predict a big cursors to disease targets, where swell of new biotech drugs anythe actual drug is then produced. time soon, most agree that they According to Samant, results of have a useful preview of the a negative control experiment kinds of drugs that will make LAB CULTURE The symbiosis of biology and chemistry indicated that plasmid could it to market over the next five in the lab has not diminished the chemist's traditional role take agene sequence into a musyears. cle. 'The results amazed the sciin formulating effective therapies. ~~ " entists," he says. "It was a para"I think what you're seeing is digm shift— the technology, management, a maturation of the industry," says Mark "The pendulum has come full way," says and board shifted, and now Vical works Monane, managing director of equity reVijay B. Samant, chief executive officer of primarily on vaccines." search at investment banking firm NeedVical, a biotech vaccines firm with 10 canham & Co. Monane points to emerging didates in the clinic. "The whole concept Samant says the plasmid D N A vaccine technologies, such as antisense RNAmedof pursuing drug development by undertechnology represents a fundamentally icines and targeted cancer vaccines, as an standing the biological processes and renew means of treatment that is of far indication that the field has come of age. lying on rational drug design has fallen greater importance than the drug target He also points to an increased sophistiapart, and people are going back to medevelopment first done at Vical. 'Targetcation of biotech start-up companies as dicinal chemistry" He emphasizes the iming is like a process improvement. Plasmid they prepare to bring their first products portance of biologists and chemists "unD N A is like a completely new synthetic
THE NEXT WAVE IN BIOPHARMACEUTICALS
The pendulum swings back to medicinal chemistry in biotech drug development
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dition, Cell Genesys is partnering with Novartis on a cancer drug, derived from a genetically modified adenovirus, that preliminarily targets bladder cancer. Despite the industry's "astounding record of success" with drugs like Herceptin and Avastin, fundamentally new treatments for breast and colon cancer, Sherwin says the time and cost of developing new technologies continue to moderate the rate at which new drugs come to market. "There will be steady progress to-
the mold. At P T C Therapeutics, for example, a drug discovery platform based on post-transcriptional control, a method of modulating RNA utilization and gene expression, has delivered candidates to the clinic in less than five years. The technology promises breakthrough therapies in several disease areas, according to CEO THAT KIND OF enthusiasm is endemic Stuart W Peltz. among the leadership at biotech firms, including Stephen A. Sherwin, CEO of Cell P T C develops small-molecule drugs Genesys, another company working in the that target the transcription apparatus of cancer vaccine field. "I'm very optimistic," human cells in order to circumvent, or Sherwin says. "It's part of the job "read through," nonsense mutaqualification." tions. Such mutations occur in BIO INJECTION D N A and produce faulty messenSherwin, an oncologist who beBiopharmaceuticals have made steady progress ger RNA. This causes the expresgan working in biotech when he to market for a decade sion ofpolypeptide chains that end joined industry pioneer Genentech prematurely, resulting in truncatin 1983, says he currently sees a New biotech drug and vaccine approvals — ed, usually nonfunctioning, pro501 ' ' ~ ~ biopharmaceutical acceleration. teins. "The drug tricks the cellular "There is an exponential increase machinery, inserts the amino acid, in the number of products coming and makes a full-length protein," out ofbiotech," he says. "Not just biPeltz explains. The technique, he ologies such as proteins and antisays, has the potential to work on bodies—and more recently cell 5-15% of patients with most getherapy—but the use of biotechnetic disorders. nology drug discovery and drug development tools to create more This year, PTC will move its lead U 8* 88 90 92 94 94 traditional small molecules." This candidate, PTC 124 for Duchenne SOURCE: Biotechnology Industry Organization acceleration will create many chalmuscular dystrophy and cystic filenges for medicinal chemistry, he brosis, into Phase II clinical trials. says. Phase I trials will begin this year on another candidate, P T C 299, an Cell Genesys' flagship technoloantiangiogenesis drug that targets gy is GVAX, a cancer vaccine platvascular endothelial growth factor, form in which irradiated whole tuagene responsible forvascular genmor cells are genetically modified eration in tumor cells. PTC has alto secrete granulocyte-macrophage so moved a hepatitis C therapy incolony-stimulating factor (GMto late-stage chemical optimization. CSF), a hormone that activates the "Our mantra has always been unimmune system to recognize and met medical need," says Peltz, notdestroy cancer cells. ing that some of PTC's therapies The technology was developed are for subsegments of small paby Somatix, which Cell Genesys tient populations—not the usual purchased in 1997. Much as Vical's purview of blockbuster drug devaccines activate muscles to provelopment. "This is personalized duce the necessary antigens and medicine," he says. "Ifou need to proteins, the GM-CSF in GVAX M AB FAB Medarex is positioned for a ramp-up in diagnose the disease; you need to jump-starts the patient's immune monoclonal antibody therapies with its bioreactor in know what type of mutation led to system. This approach obviates the Annandale, N J . the disease. Then you treat only need to pinpoint the specific antithat subpopulation that has the disease as gen that is most therapeutically important, ward success," he says. "More companies a consequence of that mutation." which is the common approach—and a will get involved. But there will be more of significant roadblock—in cancer vaccine a smooth curve in the growth ofbiotech Much of that data are available—the development. treatments rather than a step function." Cystic Fibrosis Foundation has done extensive genotyping, he says, so that 9 0 % But while many in the industry speak of W i t h the Somatix acquisition, Cell of patients know what type of mutation a 12- to 15-year period for new technologies Genesys also obtained gene therapy techcauses their disease. "The patient populato reach the market, especially in cancer nologies, which were spun off in 2001 as tion is ready" treatment, there are several approaches in Ceregene, a developer of drugs for Alzcancer and other diseases that may break heimer's and Parkinson's diseases. In adPeltz agrees that the biopharmaceutiroute," Samant says. "It's as if I came to you with a process for making ammonia at atmospheric pressure. That is a huge breakthrough, compared with a catalyst that improves my ammonia-manufacturing yield by 5%. That's the difference."
At the BIO 2005 convention in June, there was a palpable sense that biotechnology is about to deliver. WWW.CEN-0NLINE.ORG
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BUSINESS calfieldhas matured substantially over the pastfiveyears, with the focus moving from new technology platforms to the development of drugs based on these platforms. This has put some smaller biotech companies in a strong position. "If you have a platform that can be used over and over again for opportunities in drug development, that's exciting," he says. MEDICINAL CHEMISTRY figured prominently in the development of PTC's platform and drug portfolio, Peltz explains. "We have a compound library of 200,000 compounds that we screen using highthroughput techniques," he says. "We find the best leads and put medicinal chemists on them. Each program makes 3,000 to 5,000 compounds in order to get to development candidates, which is hard work done through medicinal chemistry" Medicinal chemistry is becoming increasingly important at Medarex, a firm that got its start developing fully human monoclonal antibodies (MAbs) and has turned its attention to MAb conjugates, that is, the combination of antibodies with small-molecule toxins. Creating such combinations, according to CEO Donald L. Drakeman, is a job for chemists. The firm recently increased its chemistry staff with the acquisition of intellectual property on toxins and antibodies from Corixa, a deal that brought about 2 0 key Corixa scientists. Medarex has 24 antibodies in clinical trials based on its UltiMAb fully human MAb technology "We are just seeing the beginning of the antibody revolution," Drakeman says. "Biologies are slowly but surely supplanting traditional small molecules as important new medicines for lifethreatening diseases." He notes that most major drug companies have initiated antibody programs. "This technology rally associated with antibodies will be maturing over the next 10-15 years." Drakeman acknowledges that this is slow progress for a technology discovered 30 years ago. The work ahead, he says, will center on developing a better understanding of disease mechanisms. "Mapping the genome was like creating the white pages of the phone book," he says. " % u know everybody's name and number, but you don't know who's a doctor, who's a lawyer, and who's a journalist." A genomic yellow pages is being created, he says, as researchers sort out the genes and therapeutic targets associated with specific diseases. Genomics has already generated many interesting lead targets, Drakeman says, resulting in more than 150 antibodies in 18
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the clinic industrywide. At current success rates, as many as 30 of these candidates will hit the market over the nextfiveyears, he adds. But even if they reach their targets, will these antibodies do the job? Hoping to increase their overall effectiveness, Medarex and other firms are developing payloadconjugated antibodies that bind radionuclides or chemical drugs to antibodies. Of
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the 17 MAbs approved for therapeutic use, three are conjugates, and two of those are radioconjugates. "The general consensus is that toxin conjugates will grow as a percentage of the total antibody market," says Nils Lonberg, senior vice president and scientific director at Medarex. "The reason is that there are a lot of targets that are not amenable to naked antibodies." For many drug targets, naked antibodies fail to mediate or block particular chemical signals or pathways to the cell. "The only way to turn the antibodies into real drugs is to somehow arm them," Lonberg says. Most initial antibody conjugate efforts involved radionuclides, but the procedure is costly and requires that drugs be generated immediately prior to use. Toxin conjugates, on the other hand, are chemically complicated, Lonberg says. "^Ybu have all the complications of the antibody and all the complications of the small molecule," he says. 'And it's more than just additive, ^bu often change the pharmacokinetic and pharmacodynamic profile of the antibody when you modify it by putting the conjugate on it. You have to understand all of the aspects of the metabolism of the toxin conjugate, which can be extremely complicated." The toxin conjugate is typically activated within the tumor cell, raising other complications, and the toxin is usually much more active than most small-molecule cancer therapies. "There are just a lot of moving parts to the equation," Lonberg says.
"It's a very difficult process of lead selection and lead optimization compared to working with a small molecule. It requires a team of chemists and biologists working together." In general, according to Lonberg, the profile of the medicinal chemist has risen in small biotech companies. "Medicinal chemistry has become much more sophisticated than it was 10 or 20 years ago,
Drakeman and it is much more accessible to small companies," he says. This is one of the factors changing the face—and in some ways the definition—of biotech companies, many ofwhich are combining biotech tools and medicinal chemistry to develop smallmolecule therapies. The traditional big drug firms are also beginning to play a major role in biopharmaceuticals. For example, Mylotarg, the one toxin conjugate antibody on the market, was put there by Wyeth, which has a relatively deep biopharmaceutical pipeline as well as a business in vaccines. "We are certainly interested in the next wave of agents," says Lee F. Allen, Wyeth's vice president of clinical R&D for oncology adding that the firm has large programs in antibody-targeted chemotherapies, cellsignaling pathway inhibitors, and traditional cytotoxics. Mylotarg, a treatment for acute myeloid leukemia, is a recombinant humanized antibody conjugated with calicheamicin, a powerful cytotoxic antibiotic derived from bacteria. Allen says calicheamicin is so toxic it cannot be administered to patients in its unconjugated form. Once linked to an antibody, however, it can be formulated to hit a target without affecting the rest of the patient's body "The biggest challenge, once you link a toxin to an antibody, is proving that once it gets to the target cell, it releases the toxic agent," Allen says. One key to success is an effective linking agent. According to Allen, Wyeth has developed a proprietary WWW.CEN-0NLINE.ORG
technology for linking toxins to antibodies that it is currently using in Phase I and II programs for a non-Hodgkin's lymphoma drug. But the big area ofunmet need, he says, is therapies for solid-tumor cancers. "We are trying to broaden the antibody conjugate technology into that arena by developing an antibody targeting the Lewis Y antigen in solid tumors," Allen says. "Hopefully this brings us into an area other than hematological malignancies." T h e field of cell signaling, another ^Wyeth focus, has "exploded," according to Allen. With the advent ofgenomics, there are currently about 4 0 0 cell-signaling agents in clinical trials, he says, all of which are designed to open up communication lines between cells. Wyeth's lead signaling molecule, an m T O R kinase inhibitor called temsirolimus, is currently in Phase III clinical trials for metastatic breast cancer, mantel cell lymphoma, and renal cell carcinoma—the latter being the furthest advanced. The m T O R kinase inhibitor, Allen explains, targets the P10 pathway, which is downstream from the tumor suppressor gene. "It is well-positioned in the molecule in terms of signaling," he says. Over the next five years, an increasing
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number of targeted signaling molecules will hit the market, Allen predicts. He says the challenge will be to learn how to use those molecules most effectively as single agents or in combinations with, for example, antibodies or cytotoxics. COMBINATION THERAPY, in fact, is a prominent area of biopharmaceutical R&D. Gentara, for example, has developed a technology for regulating apoptosis, or cell death, and sees a role for its therapies in boosting the effectiveness of chemotherapy drugs already in use and in development. The company, which hopes to bring its WWW.CEN-0NLINE.ORG
first cancer therapy into the clinic next year, has developed a technique called Smac mimetics for the production of small molecules that mimic the activity of a protein called second mitochondria-derived activator of caspases (Smac). Smac triggers cell death by compensating for the effect of XIAP, another protein that inhibits normal cells from undergoing apoptosis. Gentara's therapies are directed at cancer cells that don't produce enough Smac to clear the apoptosis pathway According to CEOJohn M. Gill, chemistry is the frontline science in developing Smac-mimetic drugs. Starting with a peptide structure, Gentara researchers launch a regimen of structural-based drug design. iiJ We can look at how compounds bind to the target and improve them by making specific modifications," he says. Based on the observation ofhow they bind to target sites, compounds can be modified to improve their pharmaceutical properties. "Medicinal chemistry is still the key technology in lead optimization," Gill says. Success at moving a candidate to the clinic next year would provide a good example of how new technologies are getting to market on a tighter schedule. Gentara began working on the technique only last year. The structure of the target protein crystal on which the firm's research is based was published in Nature in 2000 by Yigong Shi, a professor of molecular biology at Princeton University who cofounded Gentara and continues to consult for the firm. Mark A. McKinlay, Gentara's chief scientific officer, says the firm has made good headway by hiring scientists with a lot of experience in biopharmaceutical development. "In addition to having a good target to start with, we had people who have been in the pharmaceutical industry including medicinal chemists who know how to make compounds and home in on the right structure," McKinlay says.'And we have biologists who know how to profile quickly and get the information back to the chemists." Henry E. Blair, the CEO of Dyax, a biopharmaceutical company that employs a phage display technology platform, says an increased understanding of disease mechanisms will foster growth in drug development. "Diseases are being subsetted," he says. "Breast cancer isn't really breast cancer— any kind of cancer isn't really any sin-
gle disease, but multiple phenotypes that require different drugs." Biotechnology will provide the most effective way of developing these drugs, he says. Despite talk of a swing back to medicinal chemistry and small molecules in the biopharmaceutical sector, Blair, who cofounded Genzyme in 1981, sees a central role for antibodies and protein therapeutics. "It is extraordinarily difficult to get the same specificity with a small molecule that you can get with a protein," he says. "It is very difficult to mimic a protein-protein interaction with a small molecule, which is not totally surprising." Dyax has two recombinant proteins in clinical trials, including DX-88, a therapy for hereditary angioedema developed in partnership with Genzyme, that is currently in Phase III trials. ULTIMATELY, industry participants agree, the lines between small and large molecules are blurring—as are the lines between big pharma and biopharma. Lonberg at Medarex muses: "In the old days, abiotech was a company pursuing some kind of recombinant protein-molecule-like drug. Nowadays, it's a small company—smaller than what you'd call a pharmaceutical company It is typically a company that is not marketing its own drug, but using tools of modern molecular biology, which by itself doesn't distinguish them from pharmaceutical companies because they are using the same tools." Another blurring line may be found between chemistry and biology but industry leaders insist that both disciplines will continue to play distinct, if symbiotic, roles. Chemistry they say will not fade in a world of bourgeoning biotech. Indeed, the opposite may be the case, according to Vical's Samant. Chemistry, he notes, is a basic component of biology and may, in fact, be more suited to breakthroughs in biopharmaceutical development. "Chemists are basically risk-takers," he says. "Biologists are risk averse—they tend to take baby steps. It's the nature of the business." Such distinctions aside, what matters, in the end, are new drugs, and the risk-takers rurining biopharmaceutical firms are optimistic. "These are exciting times," says PTC's Peltz, noting that his firm has been able to move innovative drug candidates into the clinic and finally test their effectiveness in treating disease. "For muscular dystrophy and cystic fibrosis, P T C 124 would be the first drug treating the underlying cause of the disease. They are not just palliative in nature. It is very exciting to be part of that." • C & E N / A U G U S T 29, 2005
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