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.

Women's Health

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.

Key findings include:

• 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.

For Women Only 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." )

Lasofoxifene. 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.

Oncology

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."

Arzoxifene. 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.

S12911. 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.

Preos. 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.

Central Nervous System

"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."

HPV vaccine. 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.