Analysts did not seem concerned about two front-page articles in 

 alleging that Eli Lilly downplayed the side effects of its antipsychotic drug Zyprexa, and promoted its off-label use in dementia patients.

The company in recent years has been the subject of thousands of product liability suits charging that the drug causes diabetes. An attorney who represents mentally ill patients leaked internal memos and e-mails from the ongoing litigation to 

, which published above-the-fold articles Sunday and Monday.

 double whammy, calling it old news. Zyprexa's ability to cause severe weight gain has been widely reported by physicians, and has been a factor contributing to a slowdown in sales over the past year. "We're all aware...of the side effect profile of Zyprexa," said Les Funtleyder, an analyst at Miller Tabak, who added, "It does highlight the risk of Lilly's dependence on Zyprexa as one of its long-term drivers."

In a statement, Lilly defended the drug, noting that "numerous studies" have failed to show that Zyprexa (olanzapine) causes diabetes. It also defended its conduct, emphasizing that the leaked documents represent a "tiny fraction" of the 11 million pages of material submitted as part of the litigation process.

Zyprexa is not the only schizophrenia treatment to be linked to weight gain and diabetes. FDA has required side effect warnings on a slew of atypical antipsychotics, including AstraZeneca's Seroquel (quetiapine), Janssen's Risperdal (risperidone), Pfizer's Geodon (ziprasidone), Novartis' Clozaril (clozapine), and Bristol-Myers Squibb's Ablify (aripiprazole).

"There's no [side-effect-free] antipsychotic," Funtleyder said, citing the CATIE (clinical antipsychotic trials of intervention effectiveness) study, a $42.2 million federal trial that began in 2000. The study compared the efficacy, safety, and cost-effectiveness of newer atypical antipsychotics with older drugs. But CATIE researchers also found that patients on Zyprexa put on more weight and had higher glucose and lipid metabolism than patients on other atypical antipsychotics. Lilly has funded proof-of-concept studies to see if it can determine why patients put on weight--and whether the drug can be reformulated to prevent the occurrence.

The news reports, however, underscore the many challenges the company faces in maintaining the momentum of its best-selling product.

Zyprexa had worldwide sales of $3.2 billion during the first nine months of 2006--a scant one percent increase over the same period last year. 

"Zyprexa sales have slowed down in the US," said Martha Freitag, an analyst at Argus Research. "The company has been working very hard to support the product," such as emphasizing its use in acute care settings because of its fast-acting nature. But according to 

, that sense of urgency may have driven aggressive tactics to promote the drug for use in patients with dementia, an indication for which it has never been tested.

Funtleyder noted that it remains to be seen whether the documents will add to Lilly's legal woes around the drug. The company has already settled about 10,500 product liability suits related to Zyprexa, and faces at least 1,500 more in six states and Canada. The first trials are expected to commence in April.

Articles

Analysts say Times' accusatory articles on Zyprexa are nothing to get excited about.

'Old News'

FDA's guidance on expanded-access programs--revised earlier this month in response to mounting pressure from patient advocates and federal courts to increase access to experimental drugs for the terminally ill--set new standards for admitting patients and for cost recovery, allowing pharmacompanies to charge for the drugs they provide to these patients. The new guidance, however, doesn't address the murky liability issues involved in compassionate-use drug programs.

"What we've tried to do with this proposal is strike the proper balance [between safety and access]," said Janet Woodcock, FDA's deputy commissioner for operations.

Agency officials refused to comment on whether the revisions announced last week are related to an ongoing lawsuit from Abigail Alliance for Better Access to Developmental Drugs, which is arguing that terminally ill patients have a constitutional right to unapproved therapies. Instead, regulators insisted that the changes are more clarification than modification.

Many companies already have compassionate-use programs in place, spurred by philanthropic motives as well as the opportunity to collect additional data from patients who were ineligible for clinical trials.

But there are also a number of unanswered questions that need to be addressed.

"While we support approaches to make experimental drugs available...our concern [has always been]: Would this discourage patients from enrolling in clinical trials?" said Alan Goldhammer, associate vice president of regulatory affairs at PhRMA. "I don't think anyone wants to short circuit the clinical trial process."

There are also concerns about informed consent, and whether treating physicians should have a certain level of expertise to administer the therapy. And there are questions about which reactions--positive or negative--must be reported to FDA, and at what point expanded access will be permitted. "Phase I is simply looking at safety and dosing," Goldhammer said. "It might get patients hopes up."

FDA emphasized that the new "clarifications" are intended to make it easier for individuals--including those in emergency situations--and small groups to access information about experimental treatment options as well as the drugs themselves. "These [expanded access] programs in fact existed, but they were not recognized by our regulations," said Rachel Behrman, deputy director in FDA's Office of Medical Policy Center for Drug Evaluation and Research, in a press conference. "Our regulations only recognized large-scale populations toward the end of" drug development.

The revised guidelines also update the original 1987 rule to suggest that the agency will grant expanded access based on a proportional scale that takes into account the risk/benefit profile of the drug, the seriousness of the disease, and the number of patients that will be exposed to it. "There's always a tension between the need for information and the need for access," Behrman said. The larger the group, for instance, the more safety and efficacy data will be needed to grant access to an investigational drug.

The new guidelines also address the issue of cost recovery. Most companies, FDA points out, don't charge for their compassionate-use programs. The agency doesn't expect that to change, but the revisions to the guidelines provide more detail about the issue of payment. The clarification should ease the burden on small, start-up companies that want to participate in these programs.

Manufacturers would have to get written permission from FDA before charging for a treatment, and would have to provide "reasonable assurance that charging will not interfere with developing the drug for marketing purposes," such as when a large-scale compassionate-use program prevents sufficient enrollment in clinical trials.

Abigail Alliance and public interest firm Washington Legal Foundation sued FDA in 2003, arguing that seriously ill patients have a constitutional right to unapproved therapies when they've exhausted other available treatments. Although a federal appeals court's three-judge panel ruled in May in favor of the group, it agreed last month to rehear the case with all ten DC circuit court judges present.

FDA's revisions to guidelines on expanding access to experimental drugs intensify an already murky issue for pharma.

Opening the Floodgates

Merck managers typically keep details of their R&D protocols close to the vest, but at their annual investors meeting last week, they confirmed rumors that they too are developing a CETP-inhibitor, the new class of anti-cholesterol drug whose fate has darkened since Pfizer pulled its much-hyped torceptrapib from Phase III trials two weeks ago.

In announcing that Merck had entered the CETP-blocker race, the president of its research laboratories, Peter Kim, was uncharacteristically blunt about its prospects. "There is no question that there remain doubts, and that those doubts have been reinforced," he said. "We--like everyone else now--are waiting to see what additional information comes in." The company's MK-0859 has just completed an eight-week Phase IIb trial that showed no cardiovascular or blood pressure side effects.

When pressed by an analyst, Kim acknowledged that he was one of the early skeptics of CETP-inhibitors. CETP, or cholesterol ester transfer protein, is involved in converting "good" HDL cholesterol into "bad" LDL cholesterol. But studies suggest that it also has a cardio-protective function, and that inhibiting it might produce defective HDL. Pfzer's large scale study--which saw a 50 percent greater mortality rate when torceptrapib was combined with Lipitor (atorvastatin)--has raised red flags among researchers, who now fear but that the entire approach causes more harm than good.

"You really have a big unknown," Kim said. "It is a field that is moving forward in terms of the characterization of HDL cells that are produced." Pfizer had been criticized for focusing its science on torceptrapib's ability to raise HDL rather than outcome studies on whether the drug could prevent heart attacks.

Yet with the statin market crowded with brand and generic products, companies are still banking on HDL to breathe new life into the category.

"Raising HDL is a big field," said Allan Haberman, principal of Haberman Associates, a consulting firm that specializes in science and technology strategy. "People are certainly trying to do something beyond niacin," a popular HDL-raiser.

Other leading CETP-inhibitor contenders include Roche, which is developing JTT705, and Avant Immunotherapeutics, which has an anti-CETP vaccine on deck, according to Haberman.

Another approach to raising HDL involves the protein APOA-1, a major component of HDL. Pfizer-owned biotech Esperion Therapeutics is working on a recombinant version, but trials have been stalled by the expense and difficulty of making the large-molecule product. Novartis and Bruin are collaborating on a Phase I small-molecule drug that uses amino acid peptides to mimic APOA-1's effect.

All of these programs are likely to continue--cautiously--because of scant understanding of the category. "People have been arguing about this for some time," Kim said. "We have no idea what target is being hit by torceptrapib. And when you don't know what's being hit, all bets are off."

At its annual pipeline debut, the company introduced its own CETP-inhibitor--with doubts.

Pharmaceutical Executive-12-20-2006

'Old News'

Opening the Floodgates

Staying the Course