The Next Wave in Biopharmaceuticals

Since its dawning in the early 1980s, the biopharmaceutical industry has been characterized by large, slow-moving waves of new technologies coming to market. The first, consisting of vaccines and recombinant protein therapies, was followed by a monoclonal antibody wave, which after 12 years is now the dominant force bringing new biotech drugs to market.

On the horizon, however, there are several crests. The sea, in fact, is becoming rather choppy as the "next wave" in biotech shapes up to include a spate of new technologies ranging from gene therapy and cell-signaling drugs to new twists on vaccines and monoclonal antibo dies that are moving into advanced clinical trials and onto the market.

At the BIO 2005 convention in Philadelphia in June, for example, there was a palpable sense that biotechnology, long perceived as falling short on its promise of breakthrough drugs, is about to deliver. Companies that only a few years ago showcased promising new drug discovery platforms, and little else, now have their first candidates in clinical trials. While few industry watchers predict a big swell of new biotech drugs anytime soon, most agree that they have a useful preview of the kinds of drugs that will make it to market over the next five years.

"I think what you're seeing is a maturation of the industry," says Mark Monane, managing director of equity research at investment banking firm Needham & Co. Monane points to emerging technologies, such as antisense RNA medicines and targeted cancer vaccines, as an indication that the field has come of age.

He also points to an increased sophistication of biotech start-up companies as they prepare to bring their first products to market. This is true especially in partnerships with big drug companies. "Gone are the days when biotech companies partner in Phase I clinical trials for relatively low economics and loss of control," Monane says. "Partnership agreements now show the prowess of biotech companies in codevelopment and comarketing."

MUCH OF the maturity and sophistication in biotech laboratories has to do with the ascendant role of chemistry. Several industry players cite a resurgence of medicinal chemistry as biopharmaceutical companies develop drug formulations that guarantee powerful therapies will reach specific targets in the body.

"The pendulum has come full way," says Vijay B. Samant, chief executive officer of Vical, a biotech vaccines firm with 10 candidates in the clinic. "The whole concept of pursuing drug development by understanding the biological processes and relying on rational drug design has fallen apart, and people are going back to medicinal chemistry." He emphasizes the importance of biologists and chemists "understanding each others' science" and working together in the lab.

Vical develops vaccines based on a proprietary plasmid DNA technology platform. These plasmid vaccines activate skeletal muscles to manufacture desired proteins and antigens. The company has completed Phase II clinical trials on a melanoma therapy as well as Phase I trials on a cytomegalovirus treatment for bone marrow transplants. It also has an angiogenesis therapy developed with AnGes, a Japanese biopharma company, in Phase III trials.

Moreover, the National Institutes of Health recently announced that it will go forward with Phase II trials of an HIV vaccine based on Vical technology, placing a $12 million order with the company to supply the vaccine for the trials. Vical is also working with NIH on vaccines for SARS (severe acute respiratory syndrome), Ebola, and West Nile disease, with Phase I trials under way in all three areas.

Perhaps the company's most important recent milestone, however, is in protecting Canadian farm-raised salmon against infectious hematopoietic necrosis virus. Vical's licensee, Novartis affiliate Aqua Health Ltd., last month received approval from the Canadian Food Inspection Agency to sell APEX-IHN vaccine, developed using Vical's DNA technology. "It is approved in a food animal, which is a breakthrough milestone," Samant says. "It passed a lot of regulatory hurdles, which makes life easier for anything coming behind it."

Vical's plasmid DNA technology was discovered by accident, Samant says. In the 1980s, the company was developing a technique for reducing drug side effects by delivering drug precursors to disease targets, where the actual drug is then produced. According to Samant, results of a negative control experiment indicated that plasmid could take a gene sequence into a muscle. "The results amazed the scientists," he says. "It was a paradigm shift--the technology, management, and board shifted, and now Vical works primarily on vaccines."

Samant says the plasmid DNA vaccine technology represents a fundamentally new means of treatment that is of far greater importance than the drug target development first done at Vical. "Targeting is like a process improvement. Plasmid DNA is like a completely new synthetic route," 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."

THAT KIND OF enthusiasm is endemic among the leadership at biotech firms, including Stephen A. Sherwin, CEO of Cell Genesys, another company working in the cancer vaccine field. "I'm very optimistic," Sherwin says. "It's part of the job qualification."

Sherwin, an oncologist who began working in biotech when he joined industry pioneer Genentech in 1983, says he currently sees a biopharmaceutical acceleration. "There is an exponential increase in the number of products coming out of biotech," he says. "Not just biologics such as proteins and antibodies--and more recently cell therapy--but the use of biotechnology drug discovery and drug development tools to create more traditional small molecules." This acceleration will create many challenges for medicinal chemistry, he says.

Cell Genesys' flagship technology is GVAX, a cancer vaccine platform in which irradiated whole tumor cells are genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), a hormone that activates the immune system to recognize and destroy cancer cells.

The technology was developed by Somatix, which Cell Genesys purchased in 1997. Much as Vical's vaccines activate muscles to produce the necessary antigens and proteins, the GM-CSF in GVAX jump-starts the patient's immune system. This approach obviates the need to pinpoint the specific antigen that is most therapeutically important, which is the common approach--and a significant roadblock--in cancer vaccine development.

With the Somatix acquisition, Cell Genesys also obtained gene therapy technologies, which were spun off in 2001 as Ceregene, a developer of drugs for Alzheimer's and Parkinson's diseases. In addition, 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 toward success," he says. "More companies will get involved. But there will be more of a smooth curve in the growth of biotech treatments rather than a step function."

But while many in the industry speak of a 12- to 15-year period for new technologies to reach the market, especially in cancer treatment, there are several approaches in cancer and other diseases that may break the mold. At PTC 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 Stuart W. Peltz.

PTC develops small-molecule drugs that target the transcription apparatus of human cells in order to circumvent, or "read through," nonsense mutations. Such mutations occur in DNA and produce faulty messenger RNA. This causes the expression of polypeptide chains that end prematurely, resulting in truncated, usually nonfunctioning, proteins. "The drug tricks the cellular machinery, inserts the amino acid, and makes a full-length protein," Peltz explains. The technique, he says, has the potential to work on 5-15% of patients with most genetic disorders.

This year, PTC will move its lead candidate, PTC 124 for Duchenne muscular dystrophy and cystic fibrosis, into Phase II clinical trials. Phase I trials will begin this year on another candidate, PTC 299, an antiangiogenesis drug that targets vascular endothelial growth factor, a gene responsible for vascular generation in tumor cells. PTC has also moved a hepatitis C therapy into late-stage chemical optimization.

"Our mantra has always been unmet medical need," says Peltz, noting that some of PTC's therapies are for subsegments of small patient populations--not the usual purview of blockbuster drug development. "This is personalized medicine," he says. "You need to diagnose the disease; you need to know what type of mutation led to the disease. Then you treat only that subpopulation that has the disease as a consequence of that mutation."

Much of that data are available--the Cystic Fibrosis Foundation has done extensive genotyping, he says, so that 90% of patients know what type of mutation causes their disease. "The patient population is ready."

Peltz agrees that the biopharmaceutical field has matured substantially over the past five years, 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 high-throughput 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 20 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. "Biologics are slowly but surely supplanting traditional small molecules as important new medicines for life-threatening 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. "You 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 the clinic industrywide. At current success rates, as many as 30 of these candidates will hit the market over the next five years, 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 payload-conjugated antibodies that bind radionuclides or chemical drugs to antibodies. Of 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. "You have all the complications of the antibody and all the complications of the small molecule," he says. "And it's more than just additive. You 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, 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 of which are combining biotech tools and medicinal chemistry to develop small-molecule 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, cell-signaling 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 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 of unmet 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."

The field of cell signaling, another Wyeth focus, has "exploded," according to Allen. With the advent of genomics, there are currently about 400 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 mTOR 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 mTOR 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 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 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 CEO John 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. "We can look at how compounds bind to the target and improve them by making specific modifications," he says. Based on the observation of how 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 single 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, a biotech 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 running 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, PTC 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."