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Much has been said about pharma's R&D lag, but a closer look at the candidates currently in Phase III shows that what the pipeline lacks in quantity it makes up for in quality. This Pharmaceutical Executive pipeline report identifies some of the top candidates in five categories: women's health, oncology, central nervous system (CNS), cardiovascular disease (CVD), and metabolic/ endocrine diseases.	

Data on drug candidates were provided by the Pharma Solutions division of the medical publishing giant Wolters Kluwer Health, which gave Pharm Exec access to its extensive Adis RD&I database, containing a wide array of information on thousands of candidates from pre-clinical through Phase III, and by the investment bank Lehman Brothers, which tracks and evaluates numerous products in its Pharma-pipelines database. In the listings that follow, drugs are ranked by a proprietary 1-100 score, developed by Adis, that assesses clinical impact.	

Adis's ratings are based on 20 parameters and are created by editors who monitor medical literature, attend conferences, and use knowledge gained from other proprietary sources. In the Adis system, a compound with no evident advantages compared to existing treatments receives a 45 or below. A compound with modest benefits in safety, efficacy, or both receives a 45-59; a compound with important benefits, 60 or above. A rating of 80 and up suggests substantial clinical advantages; in some cases a rating of 80 means there are no alternative treatments. An Adis score of 55 was the cutoff in these listings.		

Wherever possible, the listing for a candidate also includes Lehman Brothers' assessment of the likelihood of approval (see "Chance of Success," page 66) and an assessment of potential peak sales. Without exception, in each therapeutic area, the compound with the highest projected peak sales is among the products with the top Adis ratings.	

The two highest rated compounds are a drug to treat osteoporosis and a recombinant enzyme replacement therapy in the metabolic/endocrine diseases category.

Oncology as a class has the most agents that could substantially improve therapeutic options.

Drugs with the highest projected earnings are always among the top-ranked, but not necessarily at the very top.

Drugs originated by small biotech firms benefit from out-licensing to larger companies.

A first-in-class selective progesterone receptor modulator could change the landscape of women's health.

Genomics-based drugs are among the top-ranked candidates in every therapeutic area analyzed.

Selective estrogen receptor modulator (SERM) development is prolific in the areas of oncology and osteoporosis.

Promising new CNS drugs for stroke and head injury may effectively confer neuroprotection after trauma.

Across all five therapeutic categories, two compounds are rated 86-the highest number assigned to any in this analysis. One of those is a Pfizer compound for postmenopausal osteoporosis. (See "Women's Health." )				

 This selective estrogen receptor modulator (SERM) inhibits bone loss and lowers cholesterol and is entering Phase III trials to evaluate its use in breast cancer prevention. Its projected peak sales are $1 billion a year, one of the highest in this report. Currently, the only SERM available for the prevention and treatment of osteoporosis is Eli Lilly's Evista (raloxifene), a first-in-class therapy.	

According to researchers, lasofoxifene "promises to be more potent than any other SERM." In a one-year Phase II trial, it was studied head-to-head with raloxifene. Not only did lasofoxifene increase bone mineral density (BMD) compared with placebo, but lasofoxifene .25mg was superior to raloxifene 60mg in increasing lumbar spine BMD. Moreover, the drug decreased LDL-cholesterol by 25 percent compared with a 17 percent reduction by raloxifene. Pfizer is compiling more data with Phase III clinical trials, enrolling more than 10,000 postmenopausal women to evaluate lasofoxifene's efficacy in increasing BMD and treating fracture. 		

Felicia Cosman, MD, clinical director for the National Osteoporosis Foundation says, "It would be good if the SERMs under development could show increased efficacy in reducing fractures at sites other than the spine. That's the type of clinical trial data that matters. Also, it would be better if a SERM did not cause hot flashes or increase the risk of venous thromboembolism."	

 Eli Lilly is harnessing its therapeutic experience with raloxifene in its efforts to launch another SERM, arzoxifene (rated 72), which has estrogen-agonist activity in bone and serum lipids and estrogen-antagonist activity in breast and uterine tissue. Arzoxifene is in development for osteoporosis,  breast cancer prevention, and endometrial cancer and has peak sales potential of $600 million.	

 French pharma company Servier, developer of this stromium-containing osteoporosis drug, claims that it both stimulates bone formation and inhibits bone reduction. In a three-year clinical trial with 1,649 postmenopausal women, the drug reduced the risk of new vertebral fractures by 41 percent compared with placebo. 	

In a separate 24-month study of 160 patients, women treated with S12911 experienced increased BMD at the spine (5.53 percent), femoral neck (2.46 percent), and hip (3.21 percent). Based on these studies, the safety and tolerability profile of S12911 was acceptable. The candidate has a rating of 80, a 60 percent chance of being approved in the European market, and projected peak sales of $300 million. 	

 The third osteoporosis treatment on the list is a recombinant human parathyroid hormone, which differs from currently available antiresorptive treatments because it is anabolic. That means it has the potential to reverse bone loss rather than just reduce bone resorption. Despite its subcutaneous injection administration, it has a rating of 75, a 75 percent chance of approval, and projected sales of $650 million.	

Its developer, Canadian-based NPS Pharmaceuticals, is ushering the compound through a series of safety studies to rule out carcinogenicity. In efficacy studies, patients experienced dose-dependent BMD increases of 2.4-6.9 percent at the lumbar spine. In September 2003, Phase II/III data showed that although hip BMD was unchanged after 12 months of treatment, when Preos was combined with alendronate, there were significant increases in hip BMD. Since then, however, additional data have been negative.	

 Perhaps the most exciting compound in this cluster, asoprisnil is the first selective progesterone receptor modulator (SPRM) to enter Phase III trials. Currently very few clinical data are available, but Takeda's early studies show that asoprisnil may have the potential to treat a variety of disorders, including endometriosis, fibroids, excessive uterine bleeding, and, in conjunction with HRT, to protect the breasts and endometrium. Asoprisnil's rating is 69, with a 20 percent chance of success, and a market potential of $700 million.  		

"This is an interesting class," says Whitworth. "If this agent truly does not increase endometrial thickening or the incidence of strokes or blood clots, it could be very useful, particularly in younger women."	

 Another notable compound in this group is the human papillomavirus (HPV) vaccine developed by Stressgen and in-licensed by Roche for the treatment of anal dysplasia. It elicits a CD4+-independent cytotoxic t-cell response and would be suitable for use in immunocompromised patients. Rated 60, the candidate has a 15 percent chance of approval and a potential to earn $500 million annually in sales. 	

The 395 oncology agents in the pipeline exemplify the groundbreaking research taking place on many fronts. (See "Oncology.") Likewise, the top ten selected for this report represent the breadth and depth of Phase III research and development. Of all of the therapeutic areas analyzed, oncology-with 85 compounds currently in Phase III development-is the most prolific. It also has the highest number of compounds rated 70 or above, which means that their approval would offer treatment benefits comparable with existing therapies in efficacy, safety, or both. Moreover, of all the drugs analyzed, oncology compounds have the highest projected peak sales. 		

 An oral compound for breast cancer being developed by Ortho-McNeil and the National Cancer Institute leads with a rating of 85. Fenretinide is a synthetic retinoid that has demonstrated efficacy as a chemotherapeutic agent in women with early-stage breast cancer. In a five-year study of 2,972 women with stage-one breast cancer, premenopausal women who were treated with fenrenatide experienced a reduced incidence of local recurrence and contralateral development of breast tumors relative to their placebo- treated counterparts. Yet, that finding did not hold true for postmenopausal women.	

In a separate analysis of 2,867 women with early breast cancer, women treated with 200mg of fenrenatide once daily for five years had a significantly lower risk of ovarian cancer compared with placebo-treated controls (0 vs. 6 cases). However, the effect only lasted for the duration of the intervention. Fenretanide has also been evaluated in conjunction with tamoxifen therapy, and the combination has shown positive results. In some cases, the regimen resulted in partial or complete remissions and disease stabilization.	

 Rated 80, the lead clinical candidate for Colorado-based Allos Therapeutics (ATI) has a proven efficacy that is attributable to its activity as a hemoglobin modifier. More specifically, the IV-infusion therapy increases the oxygen-carrying capacity of hemoglobin while simultaneously inducing cytotoxic effects and providing neuroprotection. Researchers believe that the adjuvant use of a radiosensitizing agent such as efaproxiral can alter the treatment landscape for those patients, partially because it does not have to cross the blood-brain barrier to be effective. 	

In a Phase II study of 69 patients with metastatic brain cancer, the first group received efaproxiral and radiotherapy, while the second group received radiotherapy alone. During follow-up, the median survival time for patients who received efaproxiral was 6.9 months compared with 4.1 months for the group receiving radiotherapy alone. The 12-month survival rate for group one was 32 percent compared with 15 percent for group two.	

 Developed by Janssen Pharmaceutica (a J&J company), this drug is the first farnesol-transferase inhibitor to enter clinical trials. As a class, farnesol-transferase inhibitors directly affect endothelial cell growth and stimulate apoptosis (programmed cell death). Along with a good tolerability profile, tipifamib has the advantage of oral dosing, but researchers warn that cancer-cell resistance to agents in this class could be a treatment-limiting problem. 	

Phase I and III clinical trials demonstrated moderate response from patients with various types of cancer. In 27 patients with previously treated advanced breast cancer, for example, tipifamib produced a partial response rate of 12 percent in patients, with a resulting stable disease rate of 35 percent. In another study, tipifamib had modest activity in patients with chronic myeloid leukemia (CML) and myelofibrosis but was inactive in patients with multiple myeloma. The drug is rated 80, has a 30 percent likelihood of approval, and projected annual peak sales of $500 million.	

 Another mechanism of action being refined in the research and development process is vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibition. A notable example of this class is vatalanib, the compound with the highest projected peak sales ($1.3 billion). 		

Novartis and collaborator Schering AG have combined forces to develop this novel agent to be used in combination with a chemotherapy regimen as part of first- and second-line treatment for metastatic colorectal cancer. Its likelihood of approval is estimated at 25 percent. Phase III trials started in April 2003, and so far vatalanib has demonstrated linear kinetics and good tolerability. 	

Early clinical trials involving more than 700 patients showed a significant reduction in tumor blood supply based on MRI imagery, and tumor vascular response was seen within 36 hours of treatment. According to Joerg Reinhardt, PhD, head of pharma development at Novartis Pharma AG, "Vatalanib is the first VEGF inhibitor, and during treatment it provides a higher level of specificity to cancer cells and less toxicity." 	

There are currently two Phase III trials testing the efficacy and safety of vatalanib. One is evaluating 1,090 patients with previously untreated colorectal cancer and the other is evaluating 830 patients with previously irinotecan-treated colorectal cancer that has progressed. 	

Still, vatalanib, along with the other top-ranking cancer agents, is intended for use as part of a combination regimen. "From an oncology perspective, we are interested in new therapies that make chemotherapy more tolerable," says Reinhardt, adding, "In the long-term, the hope is that you won't need the less specific therapy at all, but at this point that's still ten years away."	

 This is one of a few vaccines in development for cancer that are thought to elicit their response on the epitope of the antigen. Early clinical trials were promising, because patients with ovarian cancer who generated immune responses to the targeted vaccination survived longer. 	

Rated 73, Oregovomab is a monoclonal antibody that targets the ovarian tumor-associated antigen CA-125. AltaRex has partnered with Unither Pharma to extend marketing reach, and presumably, to drive the development process forward. United Therapeutics recently initiated two Phase III trials to evaluate oregovomab for the treatment of advanced ovarian cancer following successful completion of first-line treatment. 		

 Administered orally, this is the first anticancer agent derived from shark cartilage to demonstrate efficacy without serious adverse events in patients with solid tumors. Rated 71, AE 941 is yet another angiogenesis inhibitor that induces cell apoptosis. 	

 This SERM (rate at 71) shows higher selectivity for breast cancer cell lines than tamoxifen, with less hematological toxicity. Preclinical safety data are positive, but more Phase III clinical data are needed and the outlook is still uncertain. "I think that miproxifene will have a tough time competing against the aromatase inhibitors," says Pat Whitworth, MD, director of the Nashville Breast Center in Tennessee. He adds that, although it may not compete well in the market for treating postmenopausal women, there may be potential for using miproxifene to treat premenopausal women. 	

 Developed by Abbott Labs in collaboration with Eisai, this endothelin A receptor antagonist is intended for use in men with hormone-refractory prostate cancer. The likelihood of market approval for Atrasentan is 30 percent, estimated peak sales are $500 million, and its rating is 70.	

 Schering AG is seeking approval of this oral cancer treatment in Europe.  It currently has a rating of 66,  a 15-30 percent chance of approval, and a peak sales potential of $50 million annually. MS-209 has shown promising results in clinical trials for treating multidrug resistant cancer when used with paclitaxel. 	

Features

Much has been said about pharma's R&D lag, but a closer look at the candidates currently in Phase III shows that what the pipeline lacks in quantity it makes up for in quality. This Pharmaceutical Executive pipeline report identifies some of the top candidates in five categories: women's health, oncology, central nervous system (CNS), cardiovascular disease (CVD), and metabolic/ endocrine diseases.

Predicting Success: A Pipeline Report

When your father is Sidney Pestka, "the father of interferon," it's hard to grow up without learning something about the potent little protein that helps regulate the immune system. "I was surrounded by science my entire life," says his son Rob Pestka. "I worked in his laboratory. 		

Joan, Rob, and Sidney Pestka (l-r) have taken PBL from a basement start-up to a $30 million a year enterprise.	

I published a paper together with him. " And so it seems only natural that one day Rob would become CEO of PBL Therapeutics. 	

PBL stands for Pestka Biomedical Laboratories, the name Sidney and Joan Pestka (and their lawyer) gave the company they founded in their basement in 1990. What started as a sideline business of making interferons for research is now a 25-person operation with $30 million a year in revenue. Despite its success, however, the reagent business is not the Pestkas' only focus. In fact, it generates capital to fund Sidney's dream of developing individual interferons that will treat the many forms of cancer. 	

Sidney began his interferon research in 1969 when he joined the Roche Institute of Molecular Biology. During the early years, the proteins came from living donors. "We obtained white blood cells from the New York Blood Center and the MD Anderson Cancer Center," he says, "and stimulated those cells to make interferon." 				

The 1972 discovery of recombinant DNA suggested that the mass manufacture of proteins was possible and opened the door to biotherapeutics. Then in 1975, Sidney altered the course of biological research by making interferon in vitro, becoming the first scientist to produce an active human protein in a test tube. He chose interferon because it was easily measured and showed great activity in small amounts.	

"It is noteworthy," he says, "that the initial work was done because of the basic-science question: 'Can we synthesize an active humanprotein in the test tube?' It turned out that we could, which demonstrates that support of basic research is extremely important. Research that doesn't initially start out to diagnose or treat or prevent a disease can actually lead to major achievements." 		

In 1977, Sidney and his colleagues made history again by developing a method to purify proteins. The process -reverse-phase high performance liquid chromatography (HPLC)-is now a standard process in biotech, pharma, and academia. 	

"We had a big surprise when we purified interferon alpha," he recalls. "We thought we were looking for one interferon and instead we found about ten different proteins." 	

That discovery generated a substantial amount of excitement-both in research circles and among the public. Interferon was considered by many to be the "magic bullet" that would treat both viral diseases and cancer. But that dream proved to be elusive. 	

The body produces iterferon in response to a viral infection. Like all potent therapies, it comes with side effects. In fact, the headache, fever, and joint pain people experience when they have the flu are not a result of the virus but instead the result of interferon at work combating the virus. And, although interferon is currently approved to treat Hepatitis C and multiple sclerosis, its ability to treat cancers generally-which requires much greater doses-has been limited by its side effects. 				

Even though much of the industry abandoned the research, Sidney never lost faith that interferon could be used as an oncology treatment. He knew he needed to discover new and better interferons and to find a way to get more therapy into the tumor with less circulating in the body. 	

His original efforts were rewarded when, in 1986, FDA approved Roferon, the interferon Sidney had developed.  With a sense of accomplishment, he left the institute that year and began teaching at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, where he continued his research.	

Then, in 1990, at the request of the university, he and his wife Joan founded Pestka Biomedical Laboratories in the basement of their home in North Caldwell, New Jersey. Their business model was simple: Supply interferons for research purposes. They started with one client and grew the company organically. 	

Packaging and shipping interferons is not a typical home business. Joan describes the early months: "We had a freezer and a refrigerator in our basement, so we kept the products down there. To get the vials out to customers, Sid would bring home styrofoam boxes that the university was throwing out. I would run to the local ice cream store and pick up dry ice, then I would package everything on the ping pong table and bring it over to Federal Express."		

As word of their business spread and demand for their product grew, they realized they would soon run out of the interferon supply they had licensed from Roche. So they hired a part-time technician and rented a small lab space in New Brunswick. 	

"She made up the materials for us in the lab, and I would go down there once or twice a week to ship them out," Joan says. "I would do the invoicing, the collection, and all the other paperwork. As we got more customers and people found out about what we were doing, we had to get more lab space and hire more people. At the end of our stay at the incubator, we had eleven different rooms, some labs, and some office space on several floors. At that point we knew we had to consolidate. So we leased and renovated some nice laboratory space in Piscataway where we are now."	

Throughout that period, Sidney continued to carry out research and teach full time at the university while functioning as PBL's chief scientific officer, and Joan took on the roles of human resource director, bookkeeper, and general administrator. When the business began to grow beyond their ability to handle it, they asked their son Rob to run it for them. 	

Although Rob grew up with science and started out his college years as a molecular biology major, halfway through he switched to architecture and civil engineering. "I guess I had somewhat of a rebellious streak at that time," he says. "I finished my degree and actually worked in that field-architectural design, construction management, civil engineering-for about five years after graduation."				

Then his parents asked him to join PBL. "At that time, I was getting a little disenchanted with the field I was in,"  Rob recalls. "It was a pretty bad time for the construction industry and for architects in general, and I was losing some interest as well. They offered me that job, and I saw it as an interesting opportunity."	

Parents like to think they know what's best for their children, and in this case, they were right. Under Rob's leadership, the company flourished, growing from a $30,000 a year "hobby"-as Joan referred to it in the early years-to a $30 million a year enterprise. It now produces 150 products, including human and animal interferons, antibodies to interferons, assay kits, and reagents (www.interferonsource.com). 	

Once the company started making real money, the family saw it as an opportunity for Sidney to conduct research on his own terms. So they started PBL Therapeutics as a separate operating unit under the larger umbrella of PBL Biomedical Laboratories.		

"He never wanted to just be a company selling a bunch of chemicals," Rob says of his father. "He's always had the goal of making an impact on humanity through scientific developments. He developed interferon, which has been quite successful against hepatitis and multiple sclerosis. But he always felt that interferon could be very powerful in the treatment of cancer. It just never came to pass. So when we had this company growing, we took some of the profits from the sales of biochemicals and invested them into developing some of our own technologies."	

With Sidney's history of scientific breakthroughs, it's no surprise that PBL has developed cutting edge therapies and methods for delivering them. First, Sidney's team discovered "ultra interferons"-proteins produced by diseased cells that, in the lab, demonstrate 20–30 times the therapeutic activity of marketed interferon. So far, PBL has about 50 different molecules that look promising in the test tube. But potency is only one issue. 		

In 2002, President George W. Bush presented Sidney Peskta, MD, with the  National Medal of Technology for his pioneering efforts in biotechnology.				

"How do we determine which one is going to have little or no side effects?" Sidney asks. "There is no surrogate marker that we could use, even in vitro or in cell cultures. So it is challenging." Also difficult is deciding which one has the most therapeutic potential and is, therefore, the best investment to start with. "Interferons are species specific," Sidney explains. "Human interferons work in human cells, but not very well in mice, for example. The closest animals that one can use for testing are the primates, and they are very expensive. Even in primates, they don't mimic exactly the effects as in humans. So this is the paradox, the difficulty that we now have."	

But the Pestkas seem to thrive on challenges. One of their main goals is to secure $10 million in funding to support contract manufacturing and human clinical trials. They are now in the process of selecting which interferon to develop as their first product. And, in addition to seeking venture capital, the company also plans to license its proprietary delivery technologies to Big Pharma.	

Most current oncology products suffer from the same drawback: Drugs that are potent enough to kill cancer also have overwhelming side effects-if they are injected into the bloodstream and allowed to circulate throughout the body. The solution is a more targeted delivery system. Many companies are trying to find ways to sneak cancer drugs through the bloodstream, undelivered, until they reach the tumor. 				

PBL is no exception. The company has developed SuRe PD (sustained release protein delivery), which allows the ultra interferon to be injected directly into the tumor, thus bypassing a systemic reaction. The interferon is formulated into particles in a variety of states, and the active interferon is released at different times over a period of weeks. (See "A Sure Thing," page 86.) 	

"SuRe PD has applications to other proteins such as erythropoietin and human growth hormone," Rob says. Although he can't name any yet, Rob says, "We are in discussions with several companies interested in applying the technology to their proteins."	

Also nearly ready to license out is another PBL breakthrough. "We've got a third technology-that's actually quite close to the clinic-that provides a better way to label monoclonal antibodies with radioisotopes," Rob says. 	

PBL's technology uses genetically engineered radiophosphates, which retain higher activity and selectivity for tumor antigens and appear less immunogenic than antibodies radiolabeled through conventional methods. Also, radioactive emissions are confined to the tumor site, minimizing the exposure of healthcare workers and patient family members.	

With a $1.3 million grant from the National Cancer Institute, the company is conducting trials in vivo against human colon carcinoma xenografts to test its radioactive phosphate against standard-use radioactive iodine technology. If it proves successful, the application will give PBL yet another opportunity for licensing revenue.	

In June 2002, President George W. Bush presented Sidney with the National Medal of Technology for "pioneering achievements that led to the development of the biotechnology industry and for basic scientific discoveries in chemistry, biochemistry, genetic engineering and molecular biology." Some people would be satisfied and call that a lifetime achievement. Not Sidney. 		

"I would love to have an approval date within two years of the time we start human trials," he says about his first interferon candidate. "If you ask anyone in the country, they would say that's unrealistic. I'm always over-optimistic. That's what keeps me going." As Joan says about him, "His philosophy has always been that everybody can work eight hours and sleep eight hours-it's what you do with the other eight hours that determines where your life is going."	

But making interferons for research and making them for testing in humans are two different propositions. 	

To move forward, the Pestkas must raise enough capital to fund clinical studies. They must also either build or work with an FDA-approved GMP facility to manufacture the clinical trials material. Once the company begins to outsource its processes, one of the biggest challenges will be letting go. 	

"It's like a child," Joan explains. "When your children get older, you have to learn to let go of the apron strings and let them function on their own. I think it's the same when you have a business grow like PBL has."	

When your father is Sidney Pestka, "the father of interferon," it's hard to grow up without learning something about the potent little protein that helps regulate the immune system. "I was surrounded by science my entire life," says his son Rob Pestka. "I worked in his laboratory. I published a paper together with him. " And so it seems only natural that one day Rob would become CEO of PBL Therapeutics.

Pharmaceutical Executive-12-01-2003

Table of Contents

Predicting Success: A Pipeline Report

Interferons: A Family Business