Pipeline

This year's Pipeline Report profiles 32 compounds that are the early fruit of pharma's investment in targeted drug design. In diabetes, HIV, hepatitis C—and especially oncology—vibrant R&D is set to revolutionize treatment with new classes of drugs over the coming decade. We spotlight today's geeky names—the DPP-IVs and MK-0518s, the Tykerbs and Telaprevirs—that are most likely to be tomorrow's glam blockbusters. Even the year's downers—we're still waiting on Acomplia, Exubera is failing to live up to the hype—are reminders of how improvements in drug development, such as Phase 0, are helping industry in its drive to become more effective. Although riskier than squeezing me-too drugs out of proven products, targeted R&D is lighting pathways not only to cures of killer diseases but to a fresh paradigm of progress and profits, and to renewed confidence in the pharmaceutical industry. From where we stand, the future looks bright.

OPEN MOUTH, INSERT... DPP-IVs, the Latest in Diabetes Innovation

Saxagliptin Bristol-Myers Squibb

TARGET INDICATION Type-2 diabetes

DEVELOPMENT Phase III

LAUNCH DATE 2008

Redona GlaxoSmithKline

TARGET INDICATION Type-2 diabetes

DEVELOPMENT Phase III

LAUNCH DATE 2010

SSR-162369 Sanofi-Aventis

TARGET INDICATION Type-2 diabetes

DEVELOPMENT Phase I

LAUNCH DATE 2014

Unnamed Ferring Pharmaceuticals/Johnson & Johnson

TARGET INDICATION Type-2 diabetes and obesity

DEVELOPMENT Preclinical

LAUNCH DATE TBA

With adult-onset and childhood diabetes rates coinciding with staggering obesity statistics, pharma companies have embedded themselves for years in this exploding market. The latest in diabetes innovation comes in the form of oral DPP-IV (dipeptidyl peptidase-IV) inhibitors, a new class of meds designed to enhance the body's own ability to lower blood sugar levels—without causing the weight gain that plagues type-2 diabetics on TZDs (thiazolidinedione).

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The new drugs prevent the DPP-IV enzyme from doing its dirty work—blocking incretin, a hormone that turns on insulin and turns off glycogen. By opposing DPP-IV, the inhibitors indirectly prolong the incretin effect, allowing the body to reduce blood-glucose levels on its own. The new drugs, which are being developed alone and in combination with other meds, are best deployed in patients who have pre-diabetes, a condition of impaired glucose tolerance before it reaches the level of diabetes.

While nearly 30 companies have DPP-IV products in their pipelines, two have emerged as leaders of the pack: Merck's Januvia (sitagliptin), approved in October, and Novartis' Galvus (vildaglitin). Two weeks before Galvus' expected approval date, Novartis got word from FDA that the agency needs three more months to review dosing and indication data. Despite this hiccup, industry watchers expect Januvia and Galvus eventually to go head-to-head, racking up $2-to-$3 billion in annual sales each. "It's a very fair game," says Decision Resources senior pharmaceutical analyst Donny Wong. "The efficacy and side effects are about the same."

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Some trial results, though, suggest that Galvus may ultimately have an edge in efficacy. When used with other drugs, both DPP-IV inhibitors produce similar drops in HbA1c (blood glucose)—close to three percent in patients with the highest baseline HbA1c. But in one study, Galvus was as effective as TZDs—without their edema, heart-failure, and weight-gain complications. Januvia so far has proved equally gentle, but industry watchers are touting Galvus' profile as superior overall.

Other companies with DPP-IV products in their pipelines: Bristol-Myers Squibb (saxagliptin, in Phase III), GlaxoSmithKline (Redona, Phase III), and Sanofi-Aventis (SSR-162369, Phase I). Ferring Pharmaceuticals and Johnson & Johnson are also designing a DPP-IV blocker, but with a twist—it's being tested for both diabetes and obesity. –JEANNETTE PARK

ONE-SHOT WONDER: Vaccines for HIV Spark Hope—and Ethical Debates

MRKAd5 Merck

TARGET INDICATION HIV vaccine

DEVELOPMENT Phase II

VCR-HIVADVO14-00-VP & VCR-HIVDNAO16-00-VP NIH Vaccine Research Center

TARGET INDICATION HIV vaccine

DEVELOPMENT Phase II

With global HIV infections set to double to 80 million by 2010, the hunt for a vaccine is an urgent priority. But developing and testing candidates poses so many scientific, ethical, and economic challenges that pharma has been understandably cool to the concept.

As a result, the pipeline is a classic good news–bad news scenario. On the one hand, there are more molecules in play than ever—and more money, thanks to Bill and Melinda Gates' $300 million bankroll. On the other, the 30-plus contenders "are almost all based on the same approach," says Wayne Koff, vice president of R&D at the International AIDS Vaccine Initiative (IAVI). "They elicit an immune response that may blunt HIV replication. What they won't do is prevent infection."

That's not your father's vaccine. But an inexpensive one-shot method of slowing disease in large numbers of people worldwide is as good as it's likely to get for the next decade. After Sanofi-Aventis and VaxGen's 16,000-person ALVA/AIDSVAX trial went bust last year, the traditional vaccine model—stimulating antibodies to neutralize a virus before it invades cells—got kicked to the curb.

The new generation is based on a cell-mediated model pioneered by Merck's MRKAd5. It carries HIV genes in an adenovirus vector, triggering the immune system to mount a T-cell attack—and, ideally, killing HIV-infected host cells. The NIH's Virology Research Center (VCR) took the Merck model and made it a one-two punch, adding a DNA vaccine as a primer to the adenovirus booster in hopes of achieving stronger, longer protection. Both show promise, with HIV-specific T-cell responses in at least half of all recipients. Merck has fully enrolled its Phase II trials worldwide, while VCR's Phase II is nearly full. Results are due in 2008.

Critics say that most people in the developing world have been exposed to the adenovirus, raising concerns that their immune system will neutralize the vaccine along with its vector. But according to VCR head Gary Nabel, MD, "The vaccines are designed with adenovirus doses high enough to overwhelm immunity."

"If both the concept and the design work, it's a home run," says IAVI's Koff. "But if only one aspect succeeds, it's just a single." In that case, Koff adds, next up at bat will be four second-generation candidates that use the same set of HIV genes but an alternative vector.

But a home run is a relative term in HIV vaccine development. "Most of us have a very high level of skepticism around these vaccines," says John Lebbos, MD, therapeutic director of infectious diseases at Decisions Resources. "The consensus is that we need a two-pronged approach to stimulate both a cell-mediated and a neutralizing-antibody response."

IAVI's Nabel agrees. "ALVA/ AIDSVAX taught us that the antibody approach is a lot more complicated than we ever thought," he says, "so we've moved the pendulum back to basic research." While the T-cell approach holds hope, its benefits are more modest. And if it fails to pan out, what looks like a pipeline full of promises will be little more than a pipe dream. –WALTER ARMSTRONG

MK-0518 Merck

TARGET INDICATION HIV

DEVELOPMENT Phase III

LAUNCH DATE 2008

PEAK ANNUAL SALES: $450 million

Merck is set to redeem its hard-to-fathom failure to produce a single anti-HIV drug since the pandemic started 25 years ago. MK-0518 is the leader of a pack of breakthrough compounds called integrase inhibitors, and word on both the street and the Street is "blockbuster."

Sylvia Eash, Decision Resources

Merck spent a decade in the lab defining its target—the integrase enzyme that enables HIV to cut and paste its genetic material into the DNA of the human T-cell—and screening compounds to short-circuit this critical function. With MK-0518, its researchers hit the bull's eye: The small molecule puts the brakes on viral replication faster than the most potent meds on the market. Plus, it looks clean on the toxicity front because the integrase enzyme it disables is so specific.

"MK-0518 is one of the most exciting stories in HIV drug development," says Sylvia Eash, an analyst at Decision Resources. "It shows impressive potency and no serious side effects so far, and if the long-term data fulfill its promise, it's likely to be a major advance."

Merck ambitiously pitted MK-0518 in Phase III trials against Bristol-Myers Squibb market leader Sustiva (efavirenz), and 24-week data showed equal efficacy in both patients new to treatment and those struggling with resistant virus.

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But given the disappointment of last year's pipeline darlings, the CCR5 entry inhibitors, a big question mark still remains. Plus, the drug's twice-daily dosing requirement poses a risk to patient adherence—and the development of HIV resistance. In the brave, new world of the once-daily, single-pill HIV treatment, introduced last summer as Atripla, MK-0518 may need to add convenience to muscle to elbow its way to number one.

Eash expects the first integrase inhibitor to get FDA approval by late 2008, and predicts that the class (Gilead has a Phase II candidate, followed by a GSK/Shionogi in Phase I) will break the blockbuster barrier by 2012. –WA

BRAIN FLOSS: Alzheimer's Meds Pick at the Root

Alzhemed Neurochem

TARGET INDICATION Alzheimer's disease

DEVELOPMENT Phase III

LAUNCH DATE 2008

Canadian drug manufacturer Neurochem is slated to release the first disease-modifying drug for the treatment of Alzheimer's in 2008. Alzhemed (tramiprosate) is a beta-amyloid aggregation inhibitor that helps prevent molecules of amyloid from binding to each other and forming plaque that causes memory failure.

"The drugs on the market today address the symptoms of Alzheimer's, but aren't addressing the cause of neuronal death," says Andrea Witt, CNS analyst at Decision Resources. Alzhemed and other pipeline hopefuls may put the brakes on beta-amyloid accumulation in the brain, which causes neuronal death and Alzheimer's symptoms. "If a drug can prevent the build up of plaque, we have the potential to slow the onset and cognitive decline in Alzheimer's patients," says Witt. "This would be the first drug to hit the market that has an effect on the underlying cause of the disease."

Alzhemed has shown limited efficacy in Phase II trials, but has good tolerability levels in patients. Drug sales are expected to be between $2 and $3 billion by 2015. –GEORGE KORONEOS

TC-1734 AstraZeneca

TARGET INDICATION Cognition dysfunction

DEVELOPMENT Phase II

LAUNCH DATE 2011

AstraZeneca has caused a stir with its nicotinic acetylcholine antagonist, TC-1734 (ispronicline), likely to be the first drug available to treat cognitive dysfunction associated with aging, schizophrenia, and other diseases. The drug, which AstraZeneca licensed from Targacept, shares the same method of action as cigarette-smoking addiction.

"Compounds like TC activate nicotine receptor subtypes in the brain," says Jerry Buccafusco, professor of pharmacology and toxicology at the Medical College of Georgia. "By doing so they try to get some of the beneficial effects of nicotine in terms of cognition, without the cardiovascular side effects or addiction."

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In Alzheimer's, the cells that produce the neurotransmitter acetycholine begin to die off, causing increasing deficits in cognition. Most existing Alzheimer's drugs target the enzyme that breaks down acetycholine. Nicotinic medication bypasses those neurons and acts directly on the acetycholine receptors, which could prevent the neurons from dying in the first place. Current medications can improve cognition performance in a certain number of people, but that benefit declines if they stop taking the drug. TC-1734 and others in development may not only manage symptoms, but arrest the disease.

Ispronicline also offers benefits in schizophrenia. "It's not so much addressing schizophrenia symptoms, as it is the cognitive impairment in schizophrenia," says Andrea Witt, CNS analyst at Decision Resources. It binds "to the nicotinic acetylcholine receptors and enhances cognition."–GK

SILVER BULLET: Oncology Drugs Hit Many Targets

Tasigna Novartis

TARGET INDICATION Chronic myeloid leukemia

DEVELOPMENT Preregistration

LAUNCH DATE 2007

PEAK ANNUAL SALES $1 billion

For patients with chronic myeloid leukemia, Gleevec (imatinib) has proven to be something of a wonder drug, with five-year survival rates surpassing 85 percent. But Novartis believes there is room for improvement, and is working to develop a second-generation version even more selective in targeting the cancer-causing Bcr-Abl gene and its mutations. Phase II results suggest that Tasgina (nilotinib) might be effective in 46 percent of Gleevec-resistant patients—potentially with fewer side effects. Like Gleevec, which is also approved for six additional indications, the drug's mechanism of action might mean that its approved indications only scratch the surface. Tasigna "has well over $1 billion in market potential," says Heather Brilliant, an analyst at Morningstar. One wrench in earnings could be Sprycel (dasatinib), Bristol-Myers Squibb's drug that targets the same gene and was approved in June. Sprycel nabbed sales of $11 million in the first quarter of 2006. –BH

Tykerb GlaxoSmithKline

TARGET INDICATION Breast cancer

DEVELOPMENT Phase III

LAUNCH DATE 2007

PEAK ANNUAL SALES $1 billion

GSK's Tykerb (lapatinib) was the talk of the American Society of Clinical Oncology meeting this year. Phase III data showed that the drug could double the time of progression of HER-2 positive breast cancer compared with chemotherapy alone, and might also prevent the brain metastases that are associated with this type of cancer.

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While Tykerb is being tested in women who are resistant to Genentech's blockbuster drug Herceptin (trastuzumab), the two drugs might one day compete head-to-head. Tykerb has the advantage of being a small molecule—so it can be given in a more patient-friendly pill form, rather than through an infusion. "What we're seeing in the field is efforts to move toward drugs that can be delivered orally," says David Johnson, MD, director of hematology/oncology at Vanderbilt University Medical Center. "Hopefully we'll be seeing more of these in the future."

Price is also becoming an ever-more-important factor in cancer treatment decisions. As a small molecule drug, Tykerb might be cheaper to manufacture than a biologic, according to Allan Haberman, principal of Haberman Associates, a consulting firm. For these reasons, sales of Tykerb could easily surpass those of Herceptin. "It could have as great, if not greater, commercial potential," says Michael Coggins, an analyst at Wood Mackenzie. –BH

Zactima AstraZeneca

TARGET INDICATION Lung and thyroid cancer

DEVELOPMENT Phase III

LAUNCH DATE 2008

PEAK ANNUAL SALES $400 million

The problem in lung cancer is that most oncology products give patients only a few more months of life, and low quality of life," says Allan Haberman, author of a study on emerging targets in lung cancer.

AstraZeneca is trying to change that. The company's oral anti-VEGF drug has a multi-targeted mechanism of action that could prove effective in a number of cancers, including lung. Currently in clinical trials to treat small-cell and non-small-cell lung cancer, it has received orphan-drug designation for several forms of advanced thyroid cancer as well. In addition to VEGFR (vascular endothelial growth factor receptor), Zactima (vandetanib) also inhibits EGFR (epidermal growth factor receptor) and RET-kinase.

If approved, the drug would compete with Genentech's non-small-cell lung cancer drug Tarceva (erlotinib)—which is also approved for advanced pancreatic cancer—and Erbitux (cetuximab), Bristol-Myers Squibb's colorectal cancer drug, another EGFR-inhibitor.

Right now, AstraZeneca says the drug is showing "subtle" improvements in boosting survival rates and reducing side effects in lung cancer patients. But even subtle improvements in the oncology market often mean big profits for drug makers, says Michael Coggins, an analyst at Wood Mackenzie. –BH

Hep to HCV: Novartis Leads Charge in Hepatitis C

Telaprevir Vertex

TARGET INDICATION Hepatitis C

DEVELOPMENT Phase IIb, fast-track

LAUNCH DATE 2009

PEAK ANNUAL SALES $2.7 billion

Valopicitabine Idenix/Novartis

TARGET INDICATION Hepatitis C

DEVELOPMENT Phase IIb

LAUNCH DATE 2010

PEAK ANNUAL SALES $250 million

Albuferon Human Genome Sciences/Novartis

TARGET INDICATION Hepatitis C

DEVELOPMENT Phase II

LAUNCH DATE 2010

PEAK ANNUAL SALES $2 billion

Hepatitis C has long presented a golden opportunity for innovative drug development. The gold-standard therapy, a combo of pegylated interferon and ribavirin (IFN/RVN), rakes in $3 billion a year and counting, despite major downsides, including 48 weekly injections complete with a side effect dubbed "the flu from hell," a 50 percent failure rate, and a price tag of $25,000. Enter Novartis, the crafty Swiss pharma giant: To take the pulse of the HCV pipeline, just check out which compounds it's betting licensing bucks on.

Nezam Afdhal, Beth Isræl Deaconess Medical Center

The treatment picture for hep C is about to switch from black and white to color, with more options that are kinder to patients and meaner to the virus. Tomorrow's standard of care will consist of triple-drug combos that attack fast-mutating HCV from different angles, as in the model for HIV.

"As we enter the age of STAT-C—Specifically Targeted Antiviral Therapy for HCV—the future of treatment looks very promising," says Nezam Afdhal, MD, chief of hepatology and director of the Liver Center at Beth Israel Deaconess Medical Center. "These small molecules should enable us to make people negative more quickly, with fewer side effects, and increase the cure rate."

Vertex's telaprevir (VX-950), a cleanly designed protease inhibitor, is the most ambitious advance—and the one Novartis failed to nab (J&J will co-promote). The small molecule blocks an enzyme critical to HCV replication, and early data show that it clears the virus four times faster than IFN/RVN, with a 70 percent success rate and few nasty side effects. Although its current three-times-a-day oral formulation may present adherence problems, pills beat interferon injection hands down. Vertex is currently conducting two big Phase II studies to PROVE (the trial's hopeful name) that adding VX-950 to IFN/RVN cuts the virus faster and better.

Another straight-shooting antiviral, Idenix's Valopicitabine (NM-283), knocks out HCV's RNA polymerase. Nowhere near as fast-acting as the Vertex compound, Valopicitabine does have the advantage of once-daily dosing—although Phase II data found iffy gastro complications. Next up: Phase III trials pitting NM283/INF/RBV against NM283/INF as first-line and back-up.

Human Genome Sciences' HCV contestant is Albuferon, a high-tech entry in the race for the pegylated interferon market. By fusing the immune modulator with human albumin, a highly concentrated protein found in blood plasma, the savvy biotech was able to design a slow-release version. According to recent Phase II data, one shot of Albuferon every two weeks works at least as well as a once-a-week shot of pegylated interferon. Phase III studies are enrolling with double-dose monthly injections—and hoping to ACHIEVE (another winning trial name) good safety data.

Cut to Novartis and its recent hep C spending spree. The company has bought marketing dibs on four biotech-built compounds: Albuferon, Valopicitabine, and two Phase I small molecules with unique mechanisms of action. Together with its generic ribavirin Sandoz deal, this portfolio may have Novartis playing hep C bartender, mixing and matching state-of-the-art drug cocktails for years to come. –WA

PUT ON WAIT: Sanofi-Aventis' Diet-Pill Problem

Acomplia Sanofi-Aventis

TARGET INDICATION Obesity

DEVELOPMENT Preregistration

LAUNCH DATE 2007

"Any day now." That's the mantra associated with Sanofi-Aventis' much-delayed anti-obesity compound. After three years of waiting for US approval of Acomplia, drug watchers are still holding their breath. And Sanofi's domestic drug marketers are scratching their heads, wondering when they will get their turn at promoting what's being trumpeted as possibly the industry's biggest blockbuster in decades.

"No one knows and no one is saying anything," says Donny Wong, senior pharmaceutical analyst at Decision Resources. "We're now in a post-Vioxx, post-Fen Phen world, and both issues are fresh in regulator's minds."

Acomplia is a cannaboid type-1 receptor (CB1) antagonist, often referred to as the "anti-munchie drug." Originally intended to treat obesity, Acomplia's broad range of additional indications—smoking withdrawal, atherosclerosis, alcoholism, liver disorders, and schizophrenia—have expectations over the moon. But side effects like elevated risk of depression were severe enough to require further studies. Earlier this year, FDA gave Sanofi an approvable letter for use in the treatment of obesity, but a non-approvable for smoking cessation.

"Any new obesity drug will be used by millions of people," says Richard Atkinson, chief of the Obetech Obesity research center in Richmond, VA, "so FDA is being exceedingly cautious in approving the drug."

Although Acomplia has launched in seven European countries, Sanofi officials are tight-lipped about a US launch date. –JP

Symbicort AstraZeneca

TARGET INDICATION Asthma/COPD

DEVELOPMENT Approved

LAUNCH DATE 2007

Already released in Europe and slated for US launch in 2007, Symbicort (budesonide/formoterol) by AstraZeneca could be the biggest competitor to the asthma market-leader, GSK's Advair. This twice daily, inhaled medication consists of a corticosteroid—budesonide—and a bronchodilator—formoterol. In addition to curbing the onset of asthma attacks, some clinical tests have shown that Symbicort can provide relief during an attack by opening the airways for easier breathing, and by reducing swelling.

"Formoterol has a slightly faster onset of action and is more dose responsive," says Cindy Mundy, director of immune and inflammatory diseases at Decision Resources. "However, providing physicians with a compelling reason to switch to Symbicort is going to be tough."

The company is hedging its bets on formoterol, a beta-agonist that appears more effective than what's in Advair. –GK

Torcetrapib Pfizer

TARGET INDICATION Cholesterol

DEVELOPMENT Phase III

LAUNCH DATE 2011

Pfizer is staking at least part of its future on being able to extend the success of mega-blockbuster statin Lipitor (atorvastatin)—a drug that represented a quarter of the company's revenue last year. That hope is pegged on torcetrapib, a compound for atherosclerosis that Pfizer will package with Lipitor. Yet the company has hit a few snares, including early data showing that torcetrapib can raise blood pressure. For that reason, FDA is likely to require longer-term data that shows that the drug not only raises good cholesterol but also reduces heart attacks.

"The word from doctors is: What really matters is outcomes data," says Mary Argent-Katawala, senior analyst at Decision Resources.

Yet, if successful, Pfizer's proposed formulation of 40 mg of Lipitor and 60 mg of torcetrapib could be an even bigger success than Lipitor. Torcetrapib is a member of the cholesterol ester transfer protein (CETP) inhibitor class; CETP acts as a key intermediary in the distribution of cholesterol between high- and low-density lipoproteins (HDL, LDL). In theory, by blocking CETP, you improve the ratio of HDL-C to LDL-C and slow the progression of coronary heart disease. Preliminary studies show that torcetrapib/atorvastatin raised HDL ("good" cholesterol) by 56 percent and lowered LDL ("bad" cholesterol) by 27 percent. Lipitor alone lowers LDL by about 39 to 60 percent—better than the combo, but Lipitor alone doesn't provide the positive effects of increasing HDL.

Skeptics, though, charge that the "up with the good" theory on cholesterol needs further investigation. "It's not enough to believe that raising HDL is a good thing," says Chuck Farkas, a cardiovascular drug analyst at Bain & Co. "We have to see it, and it's something we haven't seen yet." –JP AND BH