Gilead, of course, is a company we’ve long been watching with interest. Here, for example, is Bill Trombetta’s look at the company in last year’s “Stealth Pharma” analysis.

Other pharma related companies in the top 50 include lab giant Waters and PBM Express Scripts.

The case as heard by the Supreme Court deals in a great deal of legal complexity, but the underlying lawsuit that inspired it is based on a fairly simple idea: Diana Levine was severely injured when she was given Wyeth’s Phenergan by a physician’s assistant who was attempting to inject the drug directly into the vein but instead either got it into the artery or injected it in such a way that it leaked out of the vein (”perivascular extravasation”) and mixed with arterial blood. The labeling for the drug warns what can happen, but Levine and her lawyers argued that Wyeth should have acted independently of FDA and contraindicated injection directly into the vein (or “IV push).

Well there are warnings, and there are warnings, so we took a look at the Phenergan PI to see what it had to say. It’ll no doubt make you feel even more sympathy for Diana Levine, but if you’re like me, it will make you wonder whether it makes sense to prevent problems with warnings when a warning like this didn’t suffice:

From the “Contraindications” section of the label:

Under no circumstances should PHENERGAN Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene (see WARNINGS—Injection Site Reactions).</b>

PHENERGAN Injection should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted following subcutaneous injection. The preferred parenteral route of administration is by deep intramuscular injection.

Under “Injection Site Reactions”:

PHENERGAN Injection can cause severe chemical irritation and damage to tissues, regardless of the route of administration. Irritation and damage can also result from perivascular extravasation, unintended intra-arterial injection, and intraneuronal or perineuronal infiltration.

Signs, Symptoms, and manifestations of severe tissue irritation include burning, pain, erythema, swelling, severe spasm of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene. Administration of PHENERGAN Injection has resulted in nerve damage ranging from temporary sensory loss to palsies and paralysis. Injection into or near a nerve may result in permanent tissue damage. In some cases, surgical intervention (including fasciotomy, skin graft, and/or amputation) may be required (see ADVERSE REACTIONS).

Inadvertent Intra-Arterial Injection
Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection. Reports compatible with unintentional intra-arterial injection of PHENERGAN Injection, usually in conjunction with other drugs intended for intravenous use suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs. Sympathetic block and heparanization have been employed during the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants. Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with PHENERGAN Injection. Use of syringes with rigid plungers or of small-bore needles might obscure typical arterial backflow if this is relied upon alone.

When used intravenously, PHENERGAN Injection should be given in a concentration of no greater than 25 mg per mL, and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of PHENERGAN Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.

Under “Adverse Reactions”:

INTRA-ARTERIAL INJECTION MAY RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.

Under “Dosage and Administration”:

The preferred parenteral route of administration for PHENERGAN Injection is by deep intramuscular injection. The proper intravenous administration of this product is well tolerated, but use of this route is not without some hazard. Not for subcutaneous administration.

UNINTENTIONAL INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY (see CONTRAINDICATIONS, WARNINGS—Injection Site Reactions). SUBCUTANEOUS INJECTION IS CONTRAINDICATED, AS IT MAY RESULT IN TISSUE NECROSIS (see CONTRAINDICATIONS, WARNINGS—Injection Site Reactions, and ADVERSE REACTIONS).

 

That was the take-away from a conversation I had the other day with John Babich, a noted radiologist and CEO of the Cambridge, MA-based biotech Molecular Insight Pharmaceuticals, which specializes in targeted radiopharmaceuticals and imaging. The company’s lead product these days is Zemiva, a radio-labeled fatty acid analog for diagnosing cardiac ischemia.

“The heart is a furnace,” Babich explains. “If there has been ischemia, metabolism shuts down.” Zemiva (a new formulation of a Japanese-developed molecule known as I-123-BMIPP) has been on the market for 10 years or so as Cardiodine. Babich’s new twist is to develop the drug to serve as a quick, reliable way to diagnose cardiac disease in the emergency room.

If you want a perfect example of how to waste money in healthcare, you could hardly choose a better example than patients who show up in the ER complaining of chest pain. Something like 4 million are admitted to hospitals each year—most of them completely unnecessarily. The problem is that it’s not easy to tell if a serious cardiac problem has taken place. A patient can show a negative EKG and negative troponins and still be in immediate danger. So a lot of people with nothing much wrong with them get admitted to intensive care units at costs of $10,000 to $20,000.

Zemiva is designed to cut down those unnecessary admissions. How? The imaging agent mimics the fat that the heart feeds on. If the heart is working normally, Zemiva is absorbed and can be seen in a SPECT scan. Molecular Imaging provides not just imaging agent, but a library of scans that a physician can use to diagnose the patient.

Pricing hasn’t been set yet, but if it falls somewhere in the range of $1,500 per patient, it’s easy to imagine that payers will jump at the chance to cut the number of ICU admits by what Babich estimates will be 80 percent or more. Think of it as rationing by accurate diagnosis.

Zemiva goes into Phase III later this year.

Waste could be defined as care that costs more than some threshold per unit of health care improvement. But what threshold? The cost of extending life by 1 year or improving its quality ranges from a few dollars to millions of dollars; and studies of the same intervention sometimes produce quite different results. Judgments will vary as to where along this continuum waste begins. Furthermore, such estimates incorporate analysts’ weightings of various outcomes and risks, which may differ from the values that patients would place on them. Most of the care that analysts label as waste is not uniformly useless but produces average benefits that are judged to be small relative to cost — and typically that cost is widely diffused among payers other than the patient.

Aaron, like almost everyone else, recommends research into what treatments are cost effective, but he also argues that cost control efforts will fail unless virtually everyone is insured. The reason? Without universal insurance, the burden of cost cutting will fall disproportionately on those who lack insurance. “If In a world with effective spending limits,” he says, “being uninsured would take on a whole new and terrifying meaning. Societal revulsion toward the resulting inequalities and deprivation would threaten the entire cost-control effort.”

Read the entire article here.

At the Prix Galien awards ceremony last month, I had the opportunity to interview the winners on camera. We’ve just posted edited versions of the interviews here. Inspiring stories, remarkable people (and some great-looking tuxes). Enjoy.

“At some point—and that point will come sooner rather than later—payers are not going to approve spending $100,000 for someone to live an extra six months,” says Erik Gordon, director of biomedicine at Stevens Institute of Technology. David Balekdjian, a partner at strategy consulting firm the Bruckner Group, confirms that “for many diseases, U.S. insurers are rigorously examining the outcomes new drugs produce, relative to their cost.” As insurers increasingly scrutinize cancer drugs, “many will never reach their markets,” Balekdjian warns.

And in case you missed it, here’s a link to a piece we published last year featuring a prescient conversation on the same topic between pharma cancer heavyweights Bruce Seeley (of Genentech), Robert LaCaze (Bristol-Myers Squibb), and Allison Ayers (Pfizer).

Photo by Lawrence Whittemore

Let the emerging market come up with low-cost must-have medicines, though, and we’ll see how long the US fights to keep them out. A handful of sucessful medicines from India and China could end up doing a remarkable amount to transform the US drug industry and US drug regulation.

I finally met a pharm exec who’s pursuing that insight as a way to build his company, when Abe Abuchowski, founder and COO of Prolong Pharmaceuticals, stopped by to visit not long ago. You’ve probably heard Abe’s name already. He’s the biotech pioneer who developed the technique of attaching polyethylene glycol (PEG) to protein-based drugs. PEGylation, the subject of Abuchowski’s thesis at Rutgers back in 1971, proved to be an effective way to reduce the immunogenecity of biotech drugs and to increase the amount of time they remained in the body, and it’s gone on to become one of the field’s gold-standard technologies.

Abuchowski himself went on to found Enzon (starting with just half a dozen people in 1983), which he developed into a fuly integrated company. “We had to,” he says. “At the time you couldn’t just hire services like toxicology.” Enzon’s pegylation technology led to several important products, including Adagen (pegylated adenosine deaminase, for severe combined immune deficiency disease, just the fifth biotech product to win FDA approval), Oncospar (pegaspargase for certain cancers), and the blockbuster PegIntron (pegylated interferon A, for Hepatitis C, developed with Schering Plough and approved in 2001).

With PegIntron, Enzon was profitable, but it turned away from pegylation, leaving the field to Nektar. (The company announced earlier this week that it was considering divesting itself of its biotech business.) Abuchowski, meanwhile, had left in 1996, spending more than a decade as a stay-at-home dad and part-time consultant. He never lost the entrepreneurial urge, though, and in 2005 launched Prolong. (The name refers in part to the way that pegylation prolongs the time a protein spends in the body.)

The new company’s strategy is to develop patented, second-generation biotech products in India and China, using Prolong’s expertise in pegylation (which Abuchowski says is not part of the Indian/Chinese biotech arsenal) and to partner with companies able to manufacture at low cost.

Low-hanging fruit is the name of his game. Within the past month or so, Prolong announced a partnership with Zydus Cadila, one of India’s 30,000 biotechs, to produce a pegylated erythropoietin (an anti-anemia drug in the same class as Amgen’s Epogen and J&J’s Procri) and another deal is in the works in India for a pegylated granulocyte colony-stimulating factor (GCSF) drug, similar to Amgen’s Neupogen. When last I spoke with Abuchowski, he was just back from China, where he formed a tentative agreement with a biotech company over one, or possibly two, products.

“All the modern technology we have here they are copying,” says Abuchoswki. “All the first generation of biotech products are being made there and brought into the marketplace. The benefit is that they are starting with scientific knowledge that is mature rather than developing that knowledge from scratch. They have the benefit of waiting for 20 years, then building the most modern facilities with the cheapest labor and developing these products at the lowest cost possible. There are an unbelievable nmber of biotech companies, and being able to link up with a company like ours will allow them to differentiate themselves from the others in the ferocious competition that goes on there.”

Expect an announcement soon. In the meantime, more news from Prolong:
The company has just received a grant from the National Heart Lung and Blood Institute to supply Prolong’s developmental blood replacement product (which, not surprisingly, is based on pegylated hemoglobin) for researchers in such areas as combat surgery.

“It’s exciting to us because it changes the dynamic of the company,” says Abuchowski. “Instead of raising money to test our product, we can sell it to the research community while still working on it as a product, and make a little money on it. And researchers will find new uses for it. We hope that various branches of the military will want to buy it for their own application.”

His bottom line is a familiar one for journalists covering the pharmaceutical industry. He writes:

“Side Effects” belongs to a genre of investigative journalism that involves talking to plaintiffs, their lawyers and their expert witnesses, taking their stories as gospel and denigrating the opposing view because corporate money (apparently less pure than money from the plaintiffs’ side) supposedly has a corrupting effect. 

It didn’t help that, as Bass herself has pointed out elsewhere, GlaxoSmithKline provided minimal input to the book. But it’s easy to understand the unwillingness of pharma companies to speak these days. The truth that they have to present is nuanced, messy, and filled with uncertainties—from clinical trials that ended up proving nothing to reports of adverse events that can’t be definitively tied to drugs but can’t be ignored. And the public, for whatever reason, seems unable to tolerate a story that gets complex and murky. Conspiracy theory reigns. As the sociologist Frank Furedi put it in a recent online article:

Contemporary conspiracy thinking helps to fuel suspicion and mistrust of politics. It replaces critical engagement with public life with a destructive search for the hidden agenda; it distracts from the clarification of genuine differences and helps turn public life into a theatre where what matters are the private lives and personal interests of mistrusted politicians. The media, in turn, fuels this attitude by continually suggesting that what really matters today is not what public figures actually say, but rather what their ‘real’ agenda is. This incites the public to look for hidden motives. No one, apparently, is what he seems to be. The normalisation of suspicion has absolutely no positive element to it.

This isn’t to say that no one’s a villain. Of course there are bad, greedy people out there. But in a world in which screwing up, misunderstanding, and outright failure seem to be the true building blocks of life, is villainy really the first hypothesis that should be on the table?

The product, which grew out of research at the M.D. Anderson Cancer Center, uses a modified adenovirus to deliver the TP53 gene to cells in the tumor, causing them to express the tumor-supressing protein P53. The drug, which is delivered into the tumor by injection, recently completed a Phase III trial in end-stage head and neck cancer. In the trial, patients with the right P53 profile showed a strong response to the drug and a good safety profile.

Gene therapies have had a hard row to hoe since 1990, when the first experiments were conducted. Effectiveness was occasionaly spectacular, but safety failures, when they’ve occurred, have been pretty spectacular too. But with significant unmet need, good biomarker support, a well-understood method of action, and strong safety data, Advexin could be the drug that gets FDA to change its mind.

One way or another, gene therapies are obviously attracting a lot of attention. Here’s a small sampling of the news from just the past couple of weeks:

• Researchers speaking at the American Urological Association explained that they had treated erectile dysfunction by injecting naked copies of the Maxi-K gene directly into penile smooth muscle. Safety is currently looking good, but the researchers want to go back with a higher dose to test efficacy.
• A Phase I trial is getting under way to test Celladon’s Mydicar in severe heart failure. The treatment involves injecting the gene that expresses the enzyme SERCA2a into the hearts of patients who underproduce it.
• Amsterdam Molecular Therapeutics announced that it has finished enrolling a pivotal trial for product AMT-011 (Glybera(R: 68.11, -0.77, -1.11%)) for Hyperlipoproteinemia. The disease, which is currently untreatable, causes patients to have a defective HPL gene, and thus fail to produce a key enzyme that breaks down fats. AMT-011 uses an adeno-associated virus to deliver healthy copies of the gene to muscle tissue.
• An Australian researcher who had previously controlled hemophilia with gene therapy, only to have the immune system undo his work far too quickly, announced that he would launch a clinical trial by the end of the year to see if he could use immunosuppression to get the body to accept the new genes.
• And finally, in a sign of just how close some observers think we are to practical gene therapy, sports officials announced that they are already on the lookout for “gene doping,” the latest, and as yet entirely hypothetical form of illegal performance enhancement.

First was Paul Tan, CEO of Living Cell Technologies, which is officially headquartered in Melbourne Australia, but operates out of Auckland, New Zealand. The company is developing a diabetes therapy that involves implanting specially encapsulated pig pancreas cells in the human body, where they can replace some of the function of the human islet cells that produce insulin.

The company uses a nifty technology to create microspheres about a half millimeter in diameter that can hold hundreds of thousands of islet cells. The microspheres, made of a seaweed-based gel, protect the cells from the immune system, and Tan says there’s hope that cells can continue to function for years. “There’s one patient who’s had an implant for ten years,” he says. “We recently tested, and they’re still producing insulin.”

The treatment, called DiabeCell, will be going into clinical trials in the US next year. So far, five insulin-dependent diabetics have been dosed with it. They averaged a 40 to 80 percent drop in the amount of insulin they needed to take. One went off insulin for several months.

It’s a fascinating and promising technology, but the key to it all is something distinctly low tech—the company’s biocertified pig herd. “They come from pigs who were abandoned on the Auckland Islands by whalers and lived isolated for 200 years,” says Tan. They’re remarkably free of viruses and parasites.” The company has created two breeding herds and maintains them in special facilities. It takes about 15 fetal pigs to treat a single patient. (The company is also exploring other therapies that make use of other cells from the pigs.) Tan expects that within the next few years the herd will be able to produce enough cells to treat 1,200 patients.

Doubling Up on Pain

“The one thing you’re never supposed to do is put two opiates together,” says John Holaday, CEO of QRx Pharma. But when researchers at the University of Queensland did just that, they discovered that lower-than-normal doses of oxycodone combined with lower-than-normal doses of other opioids, they produced good pain relief with fewer side effects.

That insight led to QRx’s lead candidate, Q8003I, an immediate-release morphine-oxycodone combination drug targeted at moderate to severe pain. The drug recently completed a placebo-controlled Phase III trial that showed it effective and well-tolerated. “There was no somnolence, no euphoria,” Holaday told me.

Holaday himself is a serial entrepreneur. He was a co-founder of Medicis in 1988, EntreMed in 1992, and launched the cell therapy company MaxCyte. How does a neuropharmacologic researcher (Holaday’s previous gig) wind up starting companies. “I had a good scientific career,” he said. “I had some patents. But I got frustrated.”

Photo by Fleur-Design