Today – Genzyme Partners With Isis, 01.09.08 – Genzyme will pay $325 million upfront — and as much as $1.9 billion — for worldwide rights to the cholesterol drug being developed by Isis Pharmaceuticals. Isis will keep a share of at least 30% of the profits, or more if sales are good. I reported that a deal between the companies looked likely in November.


Back in Nov 2007 Genzyme Eyes Isis Drug, by Matthew Herper, 11.09.07 – Isis Pharmaceuticals, developer of a promising anti-cholesterol injection that produces unprecedented drops in heart-attack causing gunk in the blood, has said it needs to sign up a marketing partner before beginning a big trial next year.

The obvious choice would be any of the drug giants who dominate the $28 billion market for cholesterol-lowering drugs. Pfizer, for one. Merck. Maybe AstraZeneca. But a surprising entrant is taking a long, hard look at Isis’ drug, previously known only as 301012 and now called mipomersen. It’s Genzyme, the biotech giant best known for selling very expensive treatments for rare and deadly genetic diseases.

Cambridge, Mass.-based Genzyme has approached cardiologists with questions about the drug’s prospects, and that the biotech giant, which has sales of $3.2 billion and a market capitalization of $20 billion, seems to be taking a keen interest in mipomersen. These doctors say Genzyme has discussed mipomersen’s prospects with them at length.

Isis says it is talking to lots of potential partners, but can’t comment on whether it is talking to any particular company. Genzyme said it would not comment on speculation about marketing deals.

But a Genzyme-Isis tie up to distribute mipomersen makes a great deal of sense. For one thing, mipomersen will at first be aimed squarely at the kind of market Genzyme understands best: an inherited genetic disease. And both companies are on the prowl for a partner. Isis needs one in order to start a large and expensive clinical trial testing its drug in patients who have high cholesterol that is not caused by a genetic defect.

Genzyme, for its part, has made acquisitions a key part of its growth strategy, with sales from products bought in from the outside generating 38% of total revenue in 2006, not to mention 50% of revenue growth, according to a research note by biotech analyst Geoffrey Porges at Sanford C. Bernstein. He counts 15 major deals going back to 1997, and he expects acquisition to remain a “core strategy.” But Porges doesn’t think Genzyme will want to spend on another major acquisition before the second half of 2008.

Thursday, Isis announced trials that could get mipomersen approved in the rare genetic disease familial hypercholesterolemia (FH). The worst form, caused by having two bad copies of a particular cholesterol gene, afflicts only a few hundred people. Their cholesterol levels can soar to six times the normal level and cause heart attacks in patients who are in their 20s.

Some 600,000 Americans have the more common form of FH, which is caused by a single bad copy of the cholesterol gene and causes levels of cholesterol that are just above the upper limit of normal. A study of both kinds of FH could be completed and filed with the U.S. Food and Drug Administration sometime next year.

Genzyme is used to selling drugs to small groups of patients for quite a lot of money. It has become one of the biggest biotech firms thanks to a series of rare diseases. Cerezyme, Genzyme’s first drug, treats a disease that afflicts fewer than 10,000 patients globally. Yet it generated $1 billion in total sales last year. Three other medicines sold by the company treat diseases that occur in just a few thousand people.

This model is so successful it is often imitated. Biomarin and Alexion have launched drugs for orphan diseases. Amicus and Shire teamed today to address some of the same markets that Genzyme targets. But Genzyme has also been moving into broader markets. The drug Renagel, for kidney dialysis, brings in $500 million a year. It already sells a drug to treat FH, Cholestagel, in Europe.

But Isis would offer Genzyme a bigger opportunity: a chance to launch a drug into a far broader market. One reason Isis needs money is the company plans to launch a study next year in patients with garden-variety high cholesterol. This study will need to be far bigger and more expensive than one in patients who suffer from FH. And while existing medicines like Lipitor, Vytorin and Crestor aren’t enough for some FH patients, they work well for most patients with run-of-the-mill high cholesterol.

There’s no guarantee that just because Genzyme is looking at Isis that it will come through with a deal. Another partner could swoop in and sign up marketing rights to mipomersen. But the companies fit nicely. Food for thought as Isis prepares to hold an analyst meeting in New York on Nov. 13.

Doctors often prescribe off-label drugs for children

By Rahul Parikh, – When a child with asthma comes to my office wheezing, he or she often needs help fast. The coughing, gasping, and hunger for air of an asthma attack call for an immediate dose of albuterol, an inhaled medication that reopens the bronchioles, or air pipes. And yet this is a prescription that the Food and Drug Administration, guardian of all things medical and pharmaceutical in this country, has not sanctioned. Amazingly, though albuterol is the drug most commonly used to treat asthma in children, it isn’t FDA-approved for them. The drug’s label reads: “Safety and effective dosing of albuterol … have not been established in children below the age of 12 years.”

Nevertheless, I prescribe this drug to kids, off-label, without reservation. I can do this because while the FDA has the authority to approve and label drugs, it cannot interfere with how doctors practice medicine. This is the right legal balance. Off-label prescriptions allow doctors to take calculated risks to help their patients. We need more of this experimentation. But drug companies and insurers are threatening to leave us with less.

I can’t imagine practicing medicine without the independence to write a prescription as I see fit. The evidence shows my colleagues agree with me: A 2006 study published in the Archives of Internal Medicine showed that in the course of a year, roughly one-fifth of prescriptions for the 169 most common drugs were for off-label uses. That comes out to a 150 million prescriptions per year.

Kids probably reap the greatest benefit from off-label prescriptions. Three-quarters of all drugs aren’t approved for them, forcing pediatricians to regularly improvise. This despite the FDA’s “pediatric rule,” which rewards drug makers with a six-month patent extension if they do studies on kids. This sounds pretty good, but since it takes a lot more than six months of money and time to complete such research, the pediatric rule is little more than a token incentive, and most companies don’t bother to take advantage of it.

Cancer patients are another big group who benefit from off-label drug use: Cancer drugs are prescribed off-label 60 percent of the time. This is essential, as Stanford oncolgist Richard Miller wrote in a recent op-ed for the Wall Street Journal: “The off label use of cancer drugs … is vital to patient care and makes important new drugs available to more patients … with different types of cancer more quickly than could occur by requiring formal clinical testing in each kind of cancer.”

Miller describes off-label uses to treat types of cancer that vary from those for which the drug has been approved, but doctors often go off-label to venture further afield, because they find that a drug has benefits in treating an entirely different condition. Such is the case with Avastin, a drug approved for colon cancer in 2004.* Soon after its approval, some clever ophthalmologists found that Avastin could help patients who were losing their eyesight because of macular degeneration. This led to widespread off-label use for that condition.

But Avastin also exemplifies the clash between a doctor’s good intentions and a drug company’s profit motive. For a patient with macular degeneration to be given Avastin, pharmacies have to compound, or specially prepare, it. Because of volume and dosing differences, that process dramatically cuts the price. Avastin costs $40 a month to treat macular degeneration instead of the $4,000 per month that the drug’s maker, Genentech, charges for colon cancer. Realizing this, Genentech submitted a compound similar to Avastin to the FDA for separate approval as a treatment for macular degeneration, calling the new drug Lucentis, which it priced at $2,000 for a month’s dose for macular degeneration.* After pretty simple comparison shopping between a $40 drug and a $2,000 drug, most ophthalmologists simply stuck with off-label Avastin. In response, Genentech recently decided to stop supplying Avastin to pharmacies that compound it.

Genentech’s typical—and tired—argument is that Avastin’s reduced off-label price cuts into profits that the company needs to develop new drugs and preserve America’s edge in health-care innovation. But even as it was cracking down on the pharmacies that were dispensing the drug more cheaply, Genentech reported a 21 percent rise in profits for the third quarter of this year—a gain it credited to strong sales of Avastin. Meanwhile, patients prescribed Lucentis have co-payments as high as $400, which makes the drug unaffordable to many of them.

The government has also started making off-label prescription more difficult, through Medicare’s effort to control drug costs. Medicare has traditionally supported off-label uses by deferring to doctors when it comes to covering the cost of prescriptions. But in recent years, Medicare started to demand the justification of an off-label prescription with formal evidence, including head-to-head trials against other drugs. The government has specifically refused to cover prescriptions for Actiq, which is FDA-approved to treat pain in cancer patients, when it’s being used to treat patients with pain with other causes. In support of this position, Medicare cites the lack of evidence that Actiq is any better than other, perhaps cheaper, pain medications.

That may make financial sense given the ever-increasing cost of prescription drugs, but Medicare risks hindering innovation. A 2006 study by MIT researchers published in the journal Pharmacotherapy showed that almost two-thirds of off-label uses resulted from “field discovery.” A doctor thinks of a new way to use a drug, trusts her intuition, tries it, and then publishes the results to alert her peers. That’s how the off-label benefits of Avastin and albuterol were discovered. How does one put a price tag on this? Medicare ought to think hard about that question before abandoning off-label coverage.

The conflict over off-label prescribing is really just another chapter in the continuing conflict between two schools of doctoring: The cottage industry of the past and the industrial-government-insurance complex of medicine’s last quarter-century. I have no illusions about who is winning here. But given the benefits, can’t we preserve a thing or two from the old days, like my authority to follow my instincts when I write a prescription?

Corrections, Jan. 7, 2008: This article originally stated, incorrectly, that Genentech submitted Avastin to the FDA for separate approval as a treatment for macular degeneration, as opposed to a compound similar to Avastin. (Return to the corrected sentence.) The article also incorrectly stated that Avastin was approved for colon cancer in 2003. (Return to the corrected sentence.)