A year of disappointments is one way to characterize the take-home message from last week's annual meeting of the American College of Cardiology, where negative drug data stole the show from nicer news.

Pfizer?s torcetrapib was the drug on everyone's mind, as the company was due to present what amounted to final autopsy results on its fallen cholesterol fighter. Ultrasounds and (real) autopsies showed that even though the CETP-inhibitor did raise HDL levels, it had no effect on atherosclerotic plaque--raising questions about whether all this extra "good cholesterol" in the blood makes any difference in preventing heart attacks and strokes.

"The substantial increase in HDL along with no significant regression in atherosclerosis was a novel finding," said Marcus Bain, an analyst at Decision Resources, adding that the data leaves researchers in the dark about whether the entire class of anti-CETP compounds will suffer from a similar all-bark, no-bite complex. Companies like Roche and Merck are staking their cardio-category futures on these drugs, and it could take several years before a verdict is reached.

AstraZeneca and partner AtheroGenics also received a gloomy prognosis for their frontrunner, AGI-1067--part of a new drug class to reduce atherosclerotic-plaque. The drug did not hit its primary Phase III endpoint: reducing cardiac events compared to a placebo.

But executives tried to buoy enthusiasm for some of the other findings, such as a decrease in the number of new diabetes cases and a decrease in cardiac death. "We believe this is certainly encouraging data," said AtheroGenics president and CEO Russell Medford, adding that the tiny biotech plans to continue development of the anti-inflammatory that as recently as December was being hailed for its "billion-dollar blockbuster potential" by Zack's Investment Research. Now Zack's is predicting that AstraZeneca will sever ties with AtheroGenics within 45 days.

Mary Argent-Katwala, an analyst at Decision Resources, is also skeptical that the clinical program can survive. "Unless they meet their primary endpoint, most doctors aren?t interested," she said.

The cardiovascular market, like the hypertension market, is entering its golden years, with cutthroat competition and an arsenal of reliable generics for doctors to try. Combination products have become trendy projects for companies in this crowded space. Merck and Schering-Plough, for instance, announced that they would be combining Zetia (ezetimibe) with atorvastatin (generic Lipitor). "In a lot of cases, it's about brand and lifecycle management," Argent-Katwala said.

Still, companies are searching for a new frontier--hence, the efforts to reduce inflammation and atherosclerotic plaque, however halting and unsteady. "That's the most active area of interest, and it's still an area that's not well understood," said Argent-Katwala.

On the brighter side, several small companies managed to shine at the high-profile confab. Isis is developing a compound (ISIS 301012) that can lower cholesterol an additional 50 percent when combined with a statin. "Those results are amazing," Argent-Katwala said. "We're predicting blockbuster status."

Bain was impressed by an ApoA-1 infusion product from Australia-based CSL Ltd. Studies have shown that people with higher levels of ApoA-1 Milano--a naturally occurring mutated strain of HDL protein discovered by accident and traced to a man in a village in northern Italy-- have a lower risk of heart disease, regardless of actual HDL levels. Although there are concerns about liver problems, investigators believe that the formulation of the drug--not the drug itself--might be to blame.

Articles

Promising drugs failed to deliver at this year's American College of Cardiology meeting.

Heartbreak at the Cardio Confab

FDA has asked Novartis to pull Zelnorm (tegaserod) from the market five years after its approval, eliciting a swift and surprised reaction from the Street and prompting debate about the role that DTC marketing might have played in the agency's decision.

Patients with severe cases of irritable bowel syndrome with constipation (IBS-C) might still be allowed to take the drug, and Novartis is stressing that there is "no causal relationship" between Zelnorm and heart attacks and stroke. "Even FDA said that this drug is appropriate for certain people with IBS-C," said Les Funtleyder, an analyst at Miller Tabak. "That sort of conciliatory tone right out of the gate kind of suggested that even they think it's a good drug."

In a research note, Funtleyder wrote, "We suspect it has as much to do with the company overmarketing the drug to consumers as it has to do with safety." Zelnorm became a household name when the Swiss drug giant began its visceral ad campaign featuring women baring their bloated stomachs with statements such as "Give me something different" penned in black Magic Marker. Bloating is one of the hallmarks of IBS-C, and patients were intended to make an immediate connection to the images. The fact that Zelnorm sales grew 37 percent in 2006 suggests that the ads hit the spot.

But not everyone agrees that the DTC ads were the culprit. "This category has had a difficult past--Lotronex, which also treats IBS, was pulled from the market and then reinstated," said Mark Senak, who specializes in regulatory issues at Fleishman-Hillard. GlaxoSmithKline's Lotronex (alosetron) was withdrawn in 2000 only to return two years later with promotion restrictions after patients protested. "I wouldn't be surprised if the same thing happens for Zelnorm. Patients in this space don't have a lot of treatment options."

Novartis is yanking Zelnorm from US and Canadian pharmacy shelves after a retrospective analysis of 18,645 patients showed more cardio events in the Zelnorm group than a placebo group (0.1 percent vs. 0.01 percent, respectively). But there are questions about the data. The rate of cardio events linked to the IBS treatment was no higher than what doctors expect to see in the general population, and occurred in patients already at high risk for heart attack and stroke.

Analysts removed Zelnorm sales from their models but were generally optimistic about its long-term prospects. "We believe the suspension of Zelnorm from the market will likely be temporary and is the result of a hyper-vigilant FDA in the post-Vioxx era," wrote A.G. Edwards analyst Joseph Tooley in a research report.

But Heather Brilliant, an analyst at Morningstar, cautioned that the sort of follow-up studies that FDA might request could take years to conduct. "This is a drug to treat a condition that's not life-threatening or severe," said. "There's no reason to take any kind of risk with a drug like this."

Still, she called the market reaction "severe"--Novartis stocks closed down 3.44 percent at $55.44 in Zurich on Monday--considering that the $561 million drug represents only about 1.5 percent of Novartis' revenue. But she added that it had been growing "very rapidly."

Funtleyder pointed to Novartis' recent approval setback with diabetes drug Galvus (vildagliptin) and generic competition to hypertension drug Lotrel (amlodipine). "You have to put this in perspective," he said. "There are a lot of other things going on."

High-profile, quick-growing IBS drug shelved because of cardio risks.

Novartis Yanks Heavily Advertised Zelnorm

GlaxoSmithKline is seeking approval for a combination vaccine that covers an unprecedented number of bacteria and virus strains in the developing world--and could be cheaper and easier to administer to children.

Globorix covers two of the most common meningitis strains in Africa's sub-Saharan "meningitis belt," where epidemics commonly take thousands of lives each year, according to the World Health Organization. More than half of meningitis cases occur in children under age 5, and the disease can cause death within 24 to 48 hours. Globorix also provides immunity against diphtheria, tetanus, pertussis, hepatitis B, and a bacteria that can cause meningitis--five antigens that GSK already packages in a separate vaccine and distributes with the help of UNICEF.

Although GSK has not set a price for Globorix, Norman Begg, the company's director of medical affairs, expects that the product will have just a "small incremental cost increase" over the five-valent vaccine. "It doesn't require any additional infrastructure [to distribute Globorix] than already exists," he said. "That's particularly important in this resource-poor region."

GSK last week submitted its application to the European Medicines Agency under a provision known as Article 58, which allows European Union regulators to approve vaccines for the developing world. If accepted, Globorix could be available early next year. Sanofi-Aventis is also working on a meningitis vaccine for the developing world.

The approval of Globorix promises to revolutionize the vaccination strategy in the meningitis belt. While the current focus is on springing into action at the first signs of an epidemic, the conjugated technology used in the vaccine will allow public health officials to immunize infants before an outbreak hits. Globorix also provides longer-term protection and can be "refreshed" with boosters--a significant advance over older polysaccharide shots, which can be given only to older children and wear off within five years.

The conjugate technology will also be used to develop a pneumonia vaccine. "GlaxoSmithKline is committed to these combination vaccines," Begg said. "This represents another step forward in our combination vaccine strategy."

New technology could revolutionize meningitis strategy in the developing world.

Pharmaceutical Executive-04-04-2007

Heartbreak at the Cardio Confab

Novartis Yanks Heavily Advertised Zelnorm

Globorix, GSK's Seven-in-One Vax