The PharmExec 2005 Pipeline Report

Pharma's future flows through the drug pipeline. And nothing speaks to changes in the industry like a new mix of drugs in development. Despite the thousands of compounds moving through clinical trials, many experts we interviewed called the industry's "lifeblood," as the pipeline truism goes, downright anemic. But even naysayers see signs of hope, pointing to promising compounds in early stages and even preclinical development.

"The industry's pipeline in general is pretty disappointing and not very significant," says Barbara Ryan, a pharmaceutical analyst and managing director at Deutsche Bank. "The pipeline looks to be fairly small relative to the size of these companies. But at the early stages of the pipeline, things are improving in sheer numbers. Companies have more products going into early stages of development than they've had in their histories."

In this year's annual report, we profile 40 drugs. Not necessarily the "Top 40," but 40 that our pharma watchers on Wall Street, at medical schools, and at the nation's top hospitals brought up again and again. A few drugs could be blockbusters: new molecules like Acomplia and Lucentis, new formulations like Exubera, even new ingredients like Traceptera, which may extend Lipitor's patent life. But we heard most about new niche drugs, especially in oncology, and new molecules for infectious-disease targets like AIDS, cervical cancer, hepatitis C, tuberculosis, and malaria. It is some of these new approaches that hold out hope for refilling the pipeline.

Acomplia [rimonabant] by Sanofi-Aventis

TARGET INDICATION

Obesity

DEVELOPMENT

Phase III

LAUNCH DATE

2006

PEAK ANNUAL SALES

$2 billion

For the second year in a row, Acomplia (rimonabant) has generated more buzz than any other drug coming through the pipeline. Even so, Sanofi-Aventis may launch its new anti-obesity compound very slowly, despite the fact that physicians are expected to prescribe the new small molecule for a wide variety of indications.

David Molowa, managing director, UBS

The cannabinoid type-1 receptor (CB1) antagonist, which is sometimes called an "anti-munchie drug" because it blocks receptors thought to trigger hunger impulses in marijuana smokers, will hit the market as the United States struggles with an unprecedented wave of obesity. But it launches in the wake of the infamous Fen-Phen (fenfluramine/phentermine) debacle, a "revolutionary" diet pill that crashed and burned. The company might also study Vioxx (rofecoxib), which floundered, in part, on Merck's decision to target too many pain indications too soon.

"Everyone wants to lose weight and the American way is to take a pill rather than exercise or diet," says Barbara Ryan of Deutsche Bank. "The efficacy of the drug looks pretty good. The question is going to be safety, and the cost in terms of safety. The mechanism of the drug would signal that there may be a problem with depression. It has the opposite effect of marijuana: As one of my colleagues says, 'Instead of getting high you get low.'"

The drug's broad range of additional indications, including smoking, perhaps alcoholism, and a host of heart-disease and insulin-related disorders often lumped together as the "metabolic syndrome," have some analysts predicting a multi-billion-dollar blockbuster. However, the drug's apparent versatility and broad marketability may harbor the seeds of its downfall, especially if unforeseen side effects surface in the early going.

"This will be a bellwether of how companies in a post-Vioxx environment are going to be more cautious in the way they promote their broad-indication products," says Murray Aitkin, senior vice president for corporate strategy at IMS Health. "I think it will also be interesting to see the DTC campaign. While there is obviously a whole program around physicians, the way this is promoted to patients will be carefully watched in the context of a post-Vioxx environment, and with an expectation that Sanofi would not begin promoting it directly to patients until six months after its launch, consistent with the PhRMA guidelines."

Acomplia's bridesmaids wait their turn

Pfizer may be the world's most formidable source of me-too blockbusters, particularly when the company starts out a few years behind the first-in-class drug.

CP-945598, Pfizer's cannabinoid CB1 antagonist, begins its lifecycle approximately six years off the pace set by Acomplia. This may not be a pure disadvantage given the company's success with Lipitor, the fifth statin to market.

The new drug was well tolerated in Phase I studies, but little is known about its efficacy, or even what sets it apart from Acomplia. Even so, the industry is watching.

"We don't have a lot of data on the Pfizer compound yet," says Deutsche Bank's Ryan. "But everyone will pursue the opportunity. Obesity is a big problem, and there are a lot of other health consequences. If you reduce your weight and all other things remain the same, cardiovascular risk will go down. Risk of diabetes will go down. And at some point, I believe that there will be a breakthrough, but where it's going to come and which one it's going to be, I don't know."

Acomplia's manufacturer, Sanofi-Aventis, has its own me-too drug positioned to profit from any shortcomings of the prospective blockbuster. In SR 147778, the company made nearly cosmetic changes, replacing a chlorine atom with a bromine and adding a CH3 group.

CP-945598 by Pfizer

Projected Launch

2012

SR 147778 by Sanofi-Aventis

Projected Launch

2010

AMG 162 [denosumab] by Amgen

TARGET INDICATION

Osteoporosis

DEVELOPMENT

Phase III

LAUNCH DATE

2008

PEAK ANNUAL SALES

$1 billion plus

A new biologic that offers convenient dosing and an innovative mechanism, denosumab reduces bone loss by decreasing the number of osteoclasts, the large cells in bone marrow responsible for breaking down bone. Some osteoporosis-trial patients experienced bone loss as a result of treatment for prostate cancer or non-metastatic breast cancer, an affliction known as treatment-induced bone loss (TIBL); others had post-menopausal osteoporosis.

Barbara Ryan, Managing Director, Deutsche Bank

"This one has really gotten a lot of buzz at the major meetings," says Sheryl Vondracek, PharmD, professor of clinical pharmacy at the University of Colorado at Denver. "The drug is going to be the first one in its class. It is an antibody against a particular binding receptor that initiates bone resorption. So it blocks the receptor that stimulates the cell that breaks down and assimilates bone."

So far, the drug has proved safe and popular at trials, not least because doses are injected just once every six months. It is slated to compete with two biphosphanates that inhibit osteoclast activity using a different mechanism. Fosamax (alendronate), a once-weekly pill, posts sales between $3 and $4 billion a year, according to ADIS. Zoledronic acid, sold as Zometa by Novartis, has sales of nearly $2 billion, and is being reformulated as a once-a-year injection, according to Vondracek.

"We expect denosumab to come in north of a billion dollars," says Molowa. "Especially if it can be launched in 2008," when the patent on Fosomax expires.

Exubera [insulin] by Pfizer/Nektar Therapeutics

TARGET INDICATION

Diabetes

LAUNCH DATE

2006

ADIS RATING

75

PEAK ANNUAL SALES

$2.25 billion

One of next year's few potential blockbusters, Exubera, an inhalable form of insulin, promises a therapeutic advance based exclusively on a new delivery system. Instead of injecting insulin when their blood sugar spikes, patients suffering from type-1 or type-2 diabetes inhale insulin powder deep into the lungs, where it is absorbed directly into the bloodstream.

Clinical data suggest that the inhaled drug takes effect about as fast as injected insulin, perhaps faster if the preparation time for IV or subcutaneous injections is taken into account. But the real advantages are convenience and comfort for patients who dislike injections and who will have a faster-acting alternative than orally administered insulin.

"It may allow patients to more appropriately manage their disease," says Ryan.

"Exubera will be very interesting in terms of a breakthrough product in short-acting inhaled insulin," says IMS' Murray Aitkin. "This means patient compliance and persistence improves."

However, Ryan warns that the new system's anticipated high price tag may be a deterrent for some patients or payers: "It will be interesting to see whether the market views the new system as a significant enough advance," she says.

Pfizer licensed the system for the inhaler and the formulation of the powdered insulin from Nektar Therapeutics, and Sanofi-Aventis will supply the insulin to Nektar for processing. Novo Nordisk and Eli Lilly also have inhaled insulin products in their pipelines, which are projected to launch in 2009 and 2010, respectively.

Lucentis [ranibizumab] by Genentech

TARGET INDICATION

Age-related macular degeneration

LAUNCH DATE

2007

PEAK ANNUAL SALES

$600 million

Hotly anticipated by clinicians, patients, and Genentech shareholders, this antibody is a fragment of the larger Avastin (bevacizumab) antibody that inhibits vascular endothelial growth factor (VEGF). The anti-angiogenic properties are similar, but the smaller molecule penetrates deeper into the eye to stem leaks in vessels that deliver blood to the retina, and stop new blood-vessel growth behind the eye.

"This is the first product that's been proven in large clinical trials to improve eyesight for the average patient with the wet form of AMD," says Molowa.

The currently marketed products, Visudyne (verteporfin) and Macugen (pegaptanib), have been shown to reduce the progression of the disease, but not to actually reverse the blindness caused by AMD.

Provenge APC 8015 by Dendreon/Kirin

TARGET INDICATION

Prostate cancer

DEVELOPMENT

Phase III

LAUNCH DATE

2007

Dendreon created a prostate cancer vaccine based on fusing common cellular components that generally occur in a successful immune response onto a dendritic cell, which usually presents an antigen. In this case, the dendritic cell carries PSA, a prostate-specific antigen, an enzyme that co-occurs with prostate cancer, and an agent that stimulates the growth of white blood cell colonies that fight the disease.

So far, the immunomodulator proved most effective for patients with a Gleason score of 7 (on a scale of 2 to 10, where 10 represents the highest likelihood that a tumor would spread). FDA has agreed that a final, ongoing Phase III study with approximately 275 patients with Gleason scores of 7—in other words, potentially the sickest patients—will provide a BLA. Kirin Brewery has licensed the vaccine.

"The preliminary data are interesting and encouraging," says Edward Gelmann, MD, an oncologist and professor of medicine at Georgetown. "But there's a huge amount of work still to be done in understanding how drugs like this are to be used in combination. The medical community, not pharma, takes up the task of mixing and matching them."

Sorafenib BAY 439006 by Onyx/Bayer

TARGET INDICATION

Cancer

DEVELOPMENT

Phase III

LAUNCH DATE

2006

ADIS RATING

83

This oncology drug was born of a rare 50/50 partnership between a Big Pharma company and one with a single drug in clinical development. This Raf kinase inhibitor also suppresses VEGF. The anti-angiogenic compound is effective against a variety of cancers, including renal-cell carcinoma, hepatocellular carcinoma, and malignant melanoma.

"FDA is basically working on this one right now," says Georgetown's Gelmann. "It has shown interesting yet unpredictable activity in renal-cell cancer, and it will be tried, I'm sure, in other cancers as well."

Onyx and Bayer submitted an NDA earlier this year. They are also exploring the drug's efficacy in combination with chemotherapy agents, and as a solo therapy for additional tumor types.

Hematide [erythropoietin mimetic] by Affymax

TARGET INDICATION

Anemia

DEVELOPMENT

Phase II

LAUNCH DATE

Unknown

CERA R-744 by Roche

TARGET INDICATION

Anemia

DEVELOPMENT

Phase III

LAUNCH DATE

2006

Hematide is a peptide that functions like erythropoietin, the hormone that stimulates peripheral stem cells in the bone marrow to produce red blood cells. But unlike natural erythropoietin, which it does not resemble in its amino-acid sequence, Hematide is stable at room temperature and can be easily manufactured. The drug is currently in Phase II trials for treatment-induced anemia in cancer and chronic-kidney-disease patients.

The new drug will compete for market share with erythropoietin α, Amgen's $4 billion drug, distributed under a variety of brand names, including Procrit.

CERA (continuous erythropoesis receptor activator), on the other hand, is a me-too biotech, according to UBS's Molowa. "It is basically the exact same thing as erythropoietin," he says. "It's just that they potentially manufacture CERA in a way that gets them around the Amgen patents." Wood McKenzie projects CERA as a billion-dollar drug by 2009, and as a strong competitor of Procrit, primarily because of its more convenient dosing regimen. CERA is administered once every three to four weeks, about half as often as erythropoietin α.

Sutent [sunitinib malate] by Pfizer

TARGET INDICATION

Cancer (GIST)

DEVELOPMENT

Phase III

LAUNCH DATE

2006

PEAK ANNUAL SALES

$750 million

Sutent, still sometimes referred to as SU-11248, is a targeted therapy that acts on a wide variety of kinase receptors with significant anti-angiogenic properties. That is, it retards the growth of tumors by slowing the production of new blood vessels. In addition to its strong clinical data, Sutent has attracted attention as Pfizer's first significant oncology launch. Although the company did not develop the drug, Sutent will be the first cancer-drug marketing campaign Pfizer designs from the beginning.

"The current companies in the oncology space will be watching Pfizer's moves very closely," says Aitken. "They have a strong reputation for their sales and marketing prowess. Other companies will be watching how they apply that to what is generally recognized as a distinctive therapy area."

Like several of its established oncology drugs, Pfizer acquired Sutent in the 2003 merger with Pharmacia. The company submitted an NDA to FDA in August for GIST (gastrointestinal stromal tumors) but the range of off-label uses may be quite broad early in the drug's lifecycle. Judah Folkman, MD, of Harvard's Children's Hospital, believes sunitinib will be used as a combination agent with Genentech's Avastin. He also notes that adding it to Gleevec has reduced resistance to that drug.

"Sutent...certainly could be a billion-dollar drug," says Ryan. "I think Pfizer specifically is building a portfolio of oncology drugs to complement that. We think over the next five years, that will be an important source of growth for Pfizer—that will be one of the focal areas the company has."

Fresh Mechanisms to Fight Resistant Viruses

NEW HIV TARGETS

L 870810 integrase inhibitor by Merck

JTK 303 integrase inhibitor by Japan Tobacco

Maraviroc entry inhibitor by Pfizer

GW 873140 entry inhibitor by GlaxoSmithKline

Vicriviroc entry inhibitor by Schering-Plough

PA 457 maturation inhibitor by Panacos

The first quarter-century of AIDS therapy produced two main classes of drugs: reverse transcriptase inhibitors and protease inhibitors. When the virus becomes resistant to these drugs, there are few options—one of which is a fusion inhibitor called Fuzeon (enfuvirtide), discovered at Duke University, and launched by Roche and Trimeris two years ago.

But now three new types of AIDS drug are in clinical trials: integrase inhibitors, which interfere with an enzyme that allows the virus to replicate and incorporate into the host DNA; CCR5 entry inhibitors, which keep the virus out of the host cell; and a maturation inhibitor that prevents the precursor viral cells from becoming fully infectious viruses.

"The interesting thing about these drugs is that they act on entirely different targets than we have studied before," says Martin S. Hirsch, MD, professor of medicine at Harvard, who saw his first AIDS patient in 1981. "What we basically have now is a number of protease inhibitors and reverse transcriptase inhibitors, so everybody is interested when a new agent comes along that gives us alternatives for resistant viruses."

Merck's L 870810 was the first integrase inhibitor, but since Merck established proof of concept last year, another half-dozen companies have begun work on similar compounds. Japan Tobacco licensed JTK 303 (beginning Phase II trials) to Gilead Sciences for milestone payments of up to $90 million plus royalties.

"Merck may be the first one out there with an integrase inhibitor, just like they were the first one out there with a protease inhibitor," says Hirsch, who worked on the original AZT clinical trials. "But the others may turn out to be better."

Even more crowded is the field of entry inhibitors—so-called CCR5 antagonists that block the virus's access to the cell by deforming a G-coupled protein receptor called CCR5 in the cell wall. Pfizer (maraviroc /UK 427857), GlaxoSmithKline (GW 873140), and Schering-Plough (vicriviroc) are all running late-stage clinical trials. Meanwhile, companies have 18 other compounds in preclinical development or early clinical trials. Clinicians are hopeful, but not all analysts believe the hype.

"These drugs are probably more important medical advances for patients than huge commercial opportunities," says Deutsche Bank's Ryan. "The HIV market is one where discounting gets fairly aggressive."

Maturation inhibitor PA 457 inhibits HIV infection by targeting the process that produces mature, infectious virus particles from infected cells. PA 457 has a distinct mechanism of action that targets a precursor protein in the virus's protective coating and disrupts its conversion to the mature protein.

TAK 242 by Takeda

TARGET INDICATION

Septic shock

DEVELOPMENT

Phase III

Designed to compete with Eli Lilly's Xigris (drotrecogin), an expensive, last-resort therapy for septic shock, Takeda Pharmaceutical's TAK 242 was granted fast-track status by FDA in July.

That was the first the US pharma industry heard of the drug. Unlike most domestic drugs, TAK 242 was not monitored closely by clinicians or academic researchers until this year, when it was already in Phase III. Wolters Kluwer's R&DI database has no informational entries before July, and lists no conference presentations and only three research articles, one from the company database and two from journals in Japan, where Takeda is based. IMS also commenced coverage in July, shortly after the FDA announcement.

"It isn't a well-known drug," said one industry insider who asked not to be named. "But the science is very strong and the drug will make serious money."

The new drug inhibits cytokine production and counteracts inflammation by suppressing the signal flow through toll-like receptor 4 (TLR4), which is one of the receptors that recognizes bacterial components, including toxins.

Xigris is a very expensive drug, says Alasdair Conn, MD, chief of emergency medicine at Massachusetts General Hospital, who was not aware of the drug until Pharm Exec called. (Xigris.com lists the average wholesale price of the therapy at $6,800.) In 2004, Xigris's worldwide sales rose 26 percent to $201 million, according to Lilly. "If this drug is indeed going head to head with Xigris, that could be a good move," Conn suggests. "Potentially, Lilly could drop the price to keep its market share."

DGJ by NIH

TARGET INDICATION

Fabry's Disease

DEVELOPMENT

Preclinical

PATIENTS IN US

Fewer than 2,000

Fabry's disease patients lack galactosidase, an enzyme that breaks down lipids. Their symptoms range from pain in the extremities to kidney or heart failure and stroke. Therapy is typically enzyme replacement. But if galactosidase is merely folded to code incorrectly for its substrate, injecting 1-deoxy-galactonojirimycin (DGJ), a "molecular chaperone," may correct the problem, says Roscoe Brady, MD, of the National Institutes of Health. The drug helps the enzyme unfold properly and catabolise lipids. "If the enzyme is present," Brady says, "the chaperone can raise levels from five to as much as 30 percent, enough to help the patient."

GW 406381 by GSK

TARGET INDICATION

Acute and chronic pain

DEVELOPMENT

Phase II

LAUNCH DATE

2009

PEAK ANNUAL SALES

$1.5 billion

Were it not for the withdrawal of Vioxx, this second-generation COX-2 inhibitor would be one of the hottest drugs in the pipeline. Early clinical data suggest that the drug will be useful for severe acute and chronic pain, since it has been shown to cross the blood-brain barrier better than existing COX-2 inhibitors.

"There clearly is a need for a non-sedative analgesic without the side effects we see with opiates," says Byron Cryer, MD, professor of medicine at Southwestern Medical School in Dallas, Texas. "We've seen lots of mechanisms that sounded attractive, but really the proof is in the Phase III clinical trials."

Clinical trials are in progress for migraine, rheumatoid arthritis, and osteoarthritis, according to GSK. But even strong clinical data may not be enough to satisfy FDA.

"The threshold for approval has changed," says Cryer, who has published journal articles on second-generation COX-2 inhibitors. "Something that was passed a few years ago may not be allowed to have the same class of evidence for approval now."

TMC 207 by Johnson & Johnson

PA-824 by Chiron/Novartis

TARGET INDICATION

Tuberculosis

LAUNCH DATE

2010

After 40 years, TB therapy is changing. To replace harsh drugs that pose toxicity, compliance, and drug-resistance problems, the Global Alliance for TB is pushing new shorter courses of therapy, including repurposing Bayer's moxifloxacin and BMS' gatifloxacin, neither of which have been tried in long-course antibiotic treatments.

TMC 207, a diarylquinalone, undermines the energy sources of myobactyerium tuberculosis by attacking ATPase, an enzyme that assembles ATP energy molecules. The Global Alliance for TB licensed PA 824 from Chiron/Novartis. A nitroimidazole, PA 824 resembles imidazoles that attack anaerobic bacteria. Further up the pipe are OPC 67683 (Otsuka), another nitroimidazole, and LL-3858 (Lupin).

TOP 10 NEW ANTI-ANGIOGENICS

A Look Into the Future of Oncology

Judah Folkman, MD, a cancer researcher at Children's Hospital of Harvard University, is the godfather of anti-angiogenic agents. While he is delighted with the success of recently approved drugs like Genentech's Avastin and Tarceva, which inhibit one or two angiogenic growth factors, he envisions a future where drugs—and the companies that make them—will work together to combat a broad range of similar proteins.

Judah Folkman, MD

"Vascular endothelial growth factor [VEGF] is made by 60 percent of human cancers," Folkman says. "Attacking that is great. But that's when the tumors start. Years later the tumors keep on making VEGF, and they also add redundant angiogenic factors. So the first thing they do is add FGF and HGF [fibroblast and hepatocyte growth factors]. In breast cancer you can have up to six angiogenic proteins coming out of one tumor."

To battle tumors generating a wide range of angiogenic proteins, oncologists will combine angiogenesis inhibitors, Folkman predicts. Avastin is already being used with Tarceva, he points out, and with low-dose chemotherapy. If new angiogenesis inhibitors are to be combined with one another, the companies that make them will have to agree on targets, compounds, and anti-angiogenic cocktails.

Folkman sees a new crop of broad-spectrum angiogenesis inhibitors, like Endostatin and Caplostatin, replacing the combination therapies. Here, Folkman offers his off-the-cuff picks, in no particular order, for the most significant new anti-angiogenic drugs.

Endostatin, a natural protein manufactured in Folkman's lab at Children's Hospital in the late 1990s. The drug was copied and improved by Chinese scientists, and approved by FDA in China for lung cancer. Big advantage: It is non-toxic, with virtually no side effects, Folkman says. Phase II trials were suspended in the United States, although patients who took the drug remained in remission for more than three years.

Caplostatin, by Children's Hospital, is Folkman's pick as the broadest anti-angiogenic agent so far. It inhibits capillary growth. However, it has not yet been manufactured for clinical trials.

ABT 510, by Abbott, mimics the anti-angiogenic activity of a naturally occurring protein, thrombospondin-1. The compound is currently in Phase II studies for lung cancer, lymphoma, renal cancer, sarcoma, and solid tumors, with a target launch date of 2008.

Lucentis, by Genentech, is a cousin of Avastin that has restored vision for age-related macular degeneration patients. (See separate profile.)

Sutent, by Pfizer, is the first major oncology launch from the world's largest pharma company. Folkman projects Sutent as a combination therapy with Avastin. (See separate profile.)

Panzem [2-methoxyestradiol], from Entremed, is a naturally occurring metabolite of estradiol, a type of estrogen. Currently in Phase II trials for prostate cancer and age-related macular degeneration, the drug was developed by one of Folkman's colleagues at Children's Hospital.

PCK 3145, by Procyon, is a synthetic peptide based on a prostate protein (PSP 94), which has anti-VEGF effects. The compound is currently in Phase II trials for prostate cancer.

Thalidomide, by Celgene, is one of the most prescribed anti-angiogenic agents in the world, if only outside the United States. Thalidomide is widely prescribed for leprosy and multiple myeloma, among other maladies. (See separate profile.)

Revlimid, by Celgene, is more potent than thalidomide, but has fewer side effects. It offers new hope for patients with resistant forms of multiple myeloma. (See separate profile.)

Zactima [vandetanib], by AstraZeneca, inhibits vascular endothelial growth factor receptor-2 (VEGFR-2). It is an orally administered anti-angiogenic agent in Phase II and III clinical trials for various solid tumors, including lung, thyroid, and breast cancer, as well as multiple myeloma.

Torcetrapib with Lipitor [atorvastatin] by Pfizer

TARGET INDICATION

Cholesterol

DEVELOPMENT

Phase III

Torcetrapib began life as a stand-alone treatment for atherosclerosis. But in the course of clinical trials, Pfizer discovered that the ester transfer protein antagonist raised levels of high-density lipids (HDL), the blood component often referred to as "good cholesterol." For the past several years, Pfizer has said little about torcetrapib as a stand-alone therapy.

Instead, the company has pushed a program to market torcetrapib as a fixed-combination cholesterol therapy with Lipitor, the top-selling drug in the world. Many analysts like the idea. If successful, the combination therapy has blockbuster potential because patients would be able to raise HDL and lower LDL, or "bad cholesterol," with one pill. The proposed formulation is 40 mg of Lipitor, with 60 mg of torcetrapib.

"There are people who would suggest that they are doing that to carry on the monopoly with Lipitor," says Ryan, noting that Lipitor faces patent expiration in 2010. "But the HDL theory may not be as well-established as the LDL theory," she says. "And HDL may be more complicated in terms of what kinds of HDL matter, and how high is high. At the end of the day, if raising HDL doesn't provide any benefit, then the combination is not compelling."

Thalomid [thalidomide] by Celgene

Revlimid [lenalidomide] by Celgene

TARGET INDICATION

Multiple myeloma

DEVELOPMENT

Phase III

Best known for causing birth defects when boomers were babies, thalidomide is making a comeback in the United States as an oncology drug. The once notorious compound is in pre-registration for multiple myeloma, a bone-marrow tumor, and in Phase III trials for indications ranging from myelodisplastic syndrome (MDS) to colorectal, lung, and renal cancers.

Murray Aitken

"Thalidomide has been a successful treatment for multiple myeloma throughout the world for the last four or five years," says Folkman of Harvard. "Now it's moving into solid tumors as an angiogenesis inhibitor. There is a report [from Celgene] that adding thalidomide to topotecan, a chemotherapy agent, is very good for ovarian cancer."

Revlimid, a derivative by Celgene that Folkman calls "the son of thalidomide," is nearing FDA approval for myelosdisplastic syndrome and multiple myeloma. An immunomodulating agent with anti-angiogenic properties, the drug appears to act directly on multiple myeloma cells that are resistant to common forms of chemotherapy.

"It's a bit of a mystery," says UBS' Molowa. "Revlimid is a highly effective agent, but it's not entirely clear how the drug works. If everything comes out well, it can be a $2 billion product."

Cheap Drugs, High Stakes

Artesunate/amodiaquine by Drugs for Neglected Diseases Initiative Foundation/Sanofi-Aventis

Artesunate/mefloquine by Drugs for Neglected Diseases Initiative Foundation

TARGET INDICATION

Malaria

LAUNCH DATE

2006

There is little malaria in the developed world. And where there is malaria, there is little money, and thus no profit motive to spur research. But because some 500 million people a year are exposed to plasmodium falciparum, the deadliest form of the mosquito-borne disease, and according to the World Health Organization, up to 2 million people die from malaria each year, researchers press ahead for new compounds.

The Drugs for Neglected Diseases Initiative Foundation, based in Switzerland, is developing two new fixed-dose single-tablet combination therapies using artesunate, a new semi-synthetic compound. They are currently in Phase III testing in Thailand, Brazil, and Burkina Faso.

"Artesunate is water soluble," says Thomas Lemke, professor of pharmacy at the University of Houston and co-editor of Foye's Principles of Medicinal Chemistry, a textbook. "That makes it unique. All the other anti-malarials are fat soluble, which puts some limitations on routes of administration, and raises stability issues."

One compound, co-developed by Sanofi-Aventis, combines 200 mg of artesunate with 270 mg of amodiaquone. The medication is expected to cost less than one dollar per adult dose and be available next year. The second blends 100 mg of artesunate with 200 mg of mefloquine.

HPV Vaccines

Gardasil by Merck

Cervarix by MedImmune/GSK

Two similar and eagerly awaited human papillomavirus (HPV) vaccines could greatly reduce cases of genital warts and cervical cancer, a disease that claims 4,000 lives each year in the United States and kills 250,000 women a year in developing countries. The two drugs use slightly different delivery procedures to introduce similar non-infective virus-like particles (VLPs) to mimic the function of HPV types 6, 11, 16, and 18. These strains, especially 16 and 18, are responsible for up to 70 percent of all cases of cervical cancer.

HPV is a sexually transmitted virus that may be carried by one-fourth of the world's population, says Paul Blumenthal, MD, of Johns Hopkins Medical Institutions, who is an advisor to a cervical-cancer screening program under development in six African nations. Since it is highly probable that most sexually active women will be exposed to the virus, some public health experts call for mass inoculations of pre-teen girls. This is expected to be an unpopular idea with many parents and some influential politicians, Blumenthal says.

However, Blumenthal argues, an effective program need not begin with children. Although the great majority of women have been exposed to the virus, almost all could still be effectively vaccinated after exposure, since the virus seldom penetrates the cellular DNA to produce the abnormal proteins that generate pre-cancerous growth. The vaccine is effective until dysplasia—the production of abnormal tissue—has begun.

Effective screening is the key to identifying patients who need early cancer treatment or, if dysplasia has not begun, who would be candidates for the vaccine, Blumenthal says. While the time-honored Pap smear may give way to a more sophisticated molecular test in the developed world, Blumenthal screens patients using a cheaper test: visual inspection with acetic acid (VIA). Ordinary household vinegar turns pre-cancerous growth on the cervix white, so it can be detected with the naked eye during a speculum exam.

Deutsche Bank's Ryan compares the new vaccines to Wyeth's pneumonia vaccine, Prevenar, which sold well in the United States, but less so in other countries: "There is clearly a big market," she says. "But it is not clear what the level of penetration will be and how quickly it happens." Important commercial factors, she says, will be how quickly the Centers for Disease Control embraces the vaccine, and whether it is universally mandated for targeted age populations.

Asenapine by Organon/Pfizer

2009 SALES

$1.1 billion

Bifuprunox by Solvay/Wyeth

2009 SALES

$960 million

Desvenlafaxine DVS-23 by Wyeth

2009 SALES

$843 million

Among current pipeline products, three of the top-six money-makers in 2009 will be psychopharmacological compounds, according to data assembled by Scottish analysts Wood Mackenzie.

Asenapine functions like clozapine as a treatment for bipolar mania and schizophrenia. Wood Mackenzie sees better efficacy for "negative" symptoms, such as flattened affect.

Bifeprunox is a dopamine receptor agonist with fewer side effects than today's drugs. In particular, it makes patients gain less weight.

"Wyeth expects to launch their new antidepressant, desvenlafaxine, in 2007," says Wood Mackenzie analyst Keith Redpath, "a year ahead of Effexor's US patent expiry in 2008."

"These drugs that are being studied are really me-too drugs," says Karl Rickels, a psychiatrist at the University of Pennsylvania School of Medicine, who specializes in depression. "But not every patient responds the same way to the same drug."

VX 950 by Vertex/Eli Lilly

TARGET INDICATION

Hepatitis C

DEVELOPMENT

Phase II

LAUNCH DATE

2011

Valopicitabine [NM 283) by Idenix/Novartis

TARGET INDICATION

Hepatitis C

DEVELOPMENT

Phase II

LAUNCH DATE

Unknown

This orally-dosed small molecule is likely to compete well against interferon, the current standard treatment for the hepatitis C virus (HCV), early clinical data suggest. The HCV protease inhibitor produced no adverse effects and appears to be free of the side effects that plague many interferon patients, especially early in treatment. These include headaches, muscle and joint aches, as well as tiredness, moodiness, and depression.

"It looks as though the mechanism could avoid side effects," says David Molowa of UBS. "The preliminary Phase II data are tantalizing. It dropped the viral titer by four logs to a virtually undetectable level."

Even so, VX 950 may turn out to be a combination therapy with interferon. "This is a chronic disease, so you have to take it chronically," Molowa says. "The biggest problem that we've encountered with other compounds for hepatitis is resistance. It will take longer-term studies before we see if we encounter resistance with this drug."

One measure of VX 950's promise: wide licensing early in its lifecycle. Eli Lilly agreed in 1997 to provide up to $50 million in research support for Vertex's development of orally active protease inhibitors. In 2004, Mitsubishi purchased rights to develop and commercialize VX 950 in Japan and other Far East countries.

Also poised to enter the hepatitis C market is valpocitabine (NM 283), an RNA polymerase inhibitor currently in Phase II studies. Designed as a once-a-day oral therapy, also probably in combination with interferon, the compound has proven active against genotype 1 of HCV, the most treatment-resistant strain of the virus.

"It's early days for these drugs," Molowa says. "So we have to wait and see. But interferon is the only game in town now. It's a multibillion-dollar market, so there's a nice opportunity for additional add-on therapies."