The big new cholesterol-lowering drug from Genzyme and Isis Pharmaceuticals, which both companies are counting on as a future profit driver, passed its first major clinical trial, but investors didn’t like what they saw when full details were released this morning at a major medical meeting.

Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS) fell 16 percent to $11.17 at 1:30 pm Eastern time after details from the trial of the drug, mipomersen, were released at the American Heart Association’s scientific sessions in Orlando, FL. Cambridge, MA-based Genzyme (NASDAQ: GENZ), which isn’t nearly as dependent on the drug, saw its shares climb 2.6 percent.

Expectations have been running high for this drug for years, with many seeing it as the next big thing for cholesterol after the invention of multi-billion dollar statin drugs such as Pfizer’s atorvastatin (Lipitor). Isis’ very bullish CEO Stanley Crooke told me last month that the drug represents an historic advance. The drug is thought to have promise because it is the first of its class that’s made of specially engineered strands of RNA drugs to block a problematic protein in the body, which often can’t be hit by conventional small-molecule drugs. In this case, mipomersen is engineered to block the production of a protein called apoB that carries the so-called “bad” LDL cholesterol in the bloodstream. The drug is originally being tested among patients with a one-in-a-million genetic condition that causes them to die young from their extremely high cholesterol, although Genzyme and Isis envision this drug becoming more widely used among wider populations of people with extremely high cholesterol that can’t be controlled by existing meds.

“Mipomersen may well be a valuable addition to the therapeutic armamentarium,” said Frederick Raal, the primary investigator of the pivotal study of mipomersen, during a webcast from today’s scientific meeting. Raal is the director of the Carbohydrate and Lipid Metabolism Research Unit at the University of the Witwatersrand in South Africa.

So what was in the data that made Isis investors, at least, skittish? First off, it should be noted that the headline results were released back in May, when Isis and Genzyme said that mipomersen reached its goal of lowering “bad” LDL cholesterol by 25 percent, compared with a 3 percent reduction on placebo, in a study of 51 patients with homozygous familial hypercholesterolemia. This meant that patients had a 100 milligram per deciliter drop in their LDL scores, which significantly lowers their risk of dangerous cardiovascular events like heart disease and stroke, Raal said. Isis and Genzyme added further detail on the effect at today’s meeting, essentially showing that secondary goals, such as lowering total cholesterol and triglycerides, also were achieved among patients on the drug.

But the treatment, which was given in a once-weekly 200 milligram injection, had some side effects worth noting. Four of the 34 patients $12 percent) who were treated with mipomersen had …Next Page »

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Isis Pharmaceuticals CEO Stanley Crooke is a man who knows how to make a grand gesture. The market may have been underwhelmed by what Isis and its partner, Genzyme, had to say about their first-of-a-kind cholesterol-lowering drug back in May, but to him that just means they’re missing the point.

When I stopped by to visit Crooke at the company’s (NASDAQ: ISIS) Carlsbad, CA, headquarters a few weeks ago to ask about his lead drug in development, mipomersen, he didn’t just offer up the usual optimistic platitudes. He said it’s going to be historic.

“In 30-plus years in drug discovery and development, I’ve been involved with 19 drugs that have made it to the market and 200 to 300 that haven’t,” Crooke says. “I’ve encountered two in my career that were amazing.”

One was cisplatinum chemotherapy for cancer. The other was cimetidine (Tagamet) for heartburn, Crooke says. “Mipomersen is the third one that’s remarkable.”

That’s a strong statement given that investors drove down Isis shares by 10 percent on heavy volume on May 20, after seeing their first glimpse of data from a pivotal trial of mipomersen. Expectations have been sky-high for this drug for a couple years now, as the next big thing for cholesterol after the invention of multi-billion dollar statin drugs such as Pfizer’s atorvastatin (Lipitor). Cambridge, MA based Genzyme (NASDAQ: GENZ) was said to outmaneuver more than a dozen rivals that wanted to co-develop mipomersen. In January 2008 Genyzme paid the princely sum of $325 million in upfront cash, plus $1.9 billion in potential milestone payments, (and potentially much more in future profit-sharing), to get a piece of ownership in this drug.

Stanley Crooke

Mipomersen has generated so much interest for at least a couple big reasons—the need for more powerful cholesterol-lowering drugs for patients who can’t get those levels under control with conventional statins, and because it represents a potential standard-bearer for Isis’ antisense technology. It’s designed to use specially engineered strands of RNA drugs to block a problematic protein in the body, which often can’t be hit by conventional small-molecule drugs. In this case, mipomersen is engineered to block the production of a protein called apoB that carries the so-called “bad” LDL cholesterol in the bloodstream.

In May, Isis and Genzyme declared victory in a press release that announced the first pivotal clinical trial of mipomersen. The companies said that of 51 patients with a rare genetic abnormality called homozygous familial hypercholesterolemia that causes high cholesterol, the drug was a success. Patients on mipomersen had a 25 percent reduction in their LDL cholesterol counts, compared with a 3 percent drop for those on a placebo. The drug also reached its secondary goals, including showing an apoB protein reduction which correlated with the cholesterol-lowering—an important point for scientists and physicians.

But the market didn’t see it as reason to cheer. Patients with this genetic abnormality are seriously ill, with LDL cholesterol scores at an eye-popping 400 milligrams per deciliter of blood when they entered the study. (Anything below 200 is considered desirable, according to the Mayo Clinic).

So simple math says that a 25 percent reduction from 400 takes those patients down to about 300, which might be good, even unprecedented for such sick patients, but it’s still not what most patients and doctors would consider healthy. Plus, there were six patients who didn’t complete their course of treatment after they were enrolled in the study, which certainly didn’t help.

So why was Crooke so enthused? He walked me through some of the context around the data that will be presented next month at the American Heart Association’s scientific sessions in Orlando, FL.

What’s remarkable, Crooke says, is that mipomersen works in every animal, and in every …Next Page »

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Oscient Pharmaceuticals has apparently run short on options to keep its struggling drug business afloat. The Waltham, MA-based biotech firm (NASDAQ:OSCI) and its subsidiary Guardian II Acquisition Corporation have each filed for Chapter 11 bankruptcy protection and Oscient has landed a buyer for one of its two marketed products, Oscient announced late yesterday.

The company says it has struck an agreement to sell its assets associated with the antibiotic drug gemifloxacin mesylate (Factive), to a subsidiary of Cary, NC-based Cornerstone Therapeutics (NASDAQ:CRTX) for more than $5 million. Yet it’s expected that there will be a competitive auction for the Factive assets in bankruptcy court before the deal is sealed. The antibiotic, which treats forms of bronchitis and pneumonia, accounted for only $16.5 million of Oscient’s $86.8 million in 2008 revenue. The firm is also seeking a buyer for its top-selling drug, fenofibrate (Antara), which is prescribed for patients with above-normal cholesterol and triglyceride levels.

Oscient appears to be the latest victim of a lousy environment for unprofitable life sciences companies searching for funds to stay alive. Other local examples include Waltham, MA-based drug developer Dynogen Pharmaceuticals, which filed for bankruptcy early this year, and synthetic DNA maker Codon Devices, which reportedly shuttered its operations in Cambridge, MA, this spring. The cash shortage has also prompted Lexington, MA-based Epix Pharmaceuticals (NASDAQ:EPIX) to sell off assets and seek other alternatives to stay afloat.

Oscient, which plans to continue operations while in bankruptcy, has racked up $183.3 million in debts and has assets valued at $174 million, according to its bankruptcy filing. The filing says that the company owes $46 million to U.S. Bank National Association, of Boston, $7.8 million to funds associated with Dallas-based investment firm Maverick Capital, $6.6 million to BB Bioventures in South San Francisco, and $5.5 million to medical products giant Abbott Labs, headquartered in Abbott Park, IL, to name its four largest creditors listed in the bankruptcy filing.

The bankruptcy filing is the latest measure Oscient has taken to keep its business intact. The company cut about 100 of its some 300 workers in February to save money, and last month it said it planned to slash another 180 jobs, including its entire 150-person sales force. Still, the company said last month that it only had enough cash to operate into the third quarter of 2009. Also, the Nasdaq plans to de-list Oscient’s common stock later this month for the company’s failure to pay fees to meet its listing obligations, according to the company.

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[[Update below]] Genzyme and Isis Pharmaceuticals have bet big on a new kind of cholesterol-lowering drug, and today the companies said it worked in a pivotal clinical trial.

Mipomersen, a drug designed to block production of a protein that carries LDL cholesterol in the blood, reached its goal in a study of 51 patients with a rare genetic abnormality called homozygous familial hypercholesterolemia, that gives them extremely high cholesterol. Patients on the new drug had a 25 percent reduction in their LDL cholesterol counts, compared with a 3 percent drop for those on placebo, and the difference was statistically significant. Full data will be presented later at a medical meeting, the companies said.

The news is important to Cambridge, MA-based Genzyme, because it is carrying out a plan to apply for FDA approval of mipomersen first in this small patient population of 500 or so, while also studying it in much larger groups of patients that might turn the product into a blockbuster. For Carlsbad, CA-based Isis Pharmaceuticals, it’s an important validation of its antisense technology, in which specially engineered strands of RNA drugs are designed to block a problematic protein in the body, which often can’t be blocked by conventional small-molecule drugs. The companies struck a partnership to co-develop the drug in January 2008, which brought $325 million in upfront cash to Isis, and could be worth as much as $1.9 billion to Isis if the drug achieves certain goals in development.

“These are promising results for a very high-risk patient population that is in great need of new treatment options,” said Genzyme chief medical officer Richard Moscicki, in a statement. “This is one of the largest studies of hoFH patients ever conducted, and we are very encouraged by these robust data and the emerging profile of the drug. With these results, we remain on-track with our development plan for mipomersen.”

Besides reaching its main goal of lowering LDL cholesterol, mipomersen achieved all three of its secondary goals in the study of reducing the apoB protein it’s supposed to block, lowering total cholesterol, and non-HDL cholesterol, the companies said. The company said it plans to submit the data to the FDA for approval in the second half of 2010, by which time it hopes to have data from larger trials of mipomersen in other types of patients with high cholesterol.

The most common side effects among the 34 patients who got mipomersen were flu-like symptoms, swelling near the injection sites, and an increase in liver enzymes. One patient dropped out of the study because of an increase in liver enzymes, which can be a sign of liver damage. Patients had to take 200 milligrams of mipomersen through weekly injections for about six months.

Patients entered the study quite sick. They had an average LDL cholesterol score of 400 milligrams per deciliter of blood, even though they were already taking the highest possible dose of the common statin medicines, and other drugs to lower fats in the bloodstream. Any total cholesterol score above 240 is considered high, and anything below 200 is considered desirable, according to the Mayo Clinic.

[[Update 11:15 am Eastern time]] A 25 percent average reduction in LDL scores would bring patients in this study down to an average score of 300 milligrams per deciliter, which for most people is still considered high. Some patients in the trial had their LDL counts drop much more than 25 percent, although those detailed results aren’t being released yet, says Isis spokeswoman Amy Blackley. “There were some really high reductions,” Blackley says.

A previous study showed the drug could lower cholesterol by an average of 49 percent—better than results announced today—but that was in just eight patients, and they took a higher 300 milligram dose, said Isis spokeswoman Amy Blackley. The pivotal study announced today was designed to show at least a 20 percent reduction, and cleared that average hurdle, even when handicapped by factoring in six patients who enrolled but didn’t complete their course of treatment, Blackley says.

“These are patients who are on everything and they still can’t get their LDL down. If you can get it down by 100 points, that’s phenomenal. There’s nothing else for them,” she says.

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Genzyme (NASDAQ:GENZ) and Isis Pharmaceuticals (NASDAQ:ISIS) say the biotech firms have begun two new late-stage clinical trials and have started screening patients for a third new study of cholesterol-lowering drug mipomersen, aiming to ratchet up the amount of data on patients treated with the drug over the next 18 months. Luke caught up with Cambridge, MA-based Genzyme last year to discuss the large biotech firm’s foray into the multibillion-dollar market for drugs that lower cholesterol with mipomersen-developer Isis, headquartered in San Diego.

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Genzyme has built an empire by thinking small—treating diseases that affect tiny groups of patients. Now it’s seeking to capitalize on a cholesterol-lowering drug that requires it to think small and big at the same time.

The Cambridge, MA-based biotech company (NASDAQ: GENZ) is starting to show how it intends to make mipomersen into a workhorse for much of its growth over the next decade. I got some insight into the company’s thinking during an interview with John Butler, president of the company’s renal, endocrinology, and cardiovascular business.

Genzyme placed a big bet on mipomersen back in January, when it agreed to pay $325 million upfront to Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS) for the right to co-market the drug worldwide. The price for a piece of mipomersen was high for a couple reasons. Soaring cholesterol levels in the fast-food-loving U.S. contribute to heart disease, the nation’s leading cause of death. And drugs that lower cholesterol are the best-selling class of pharmaceutical products, generating 79 million prescriptions a year, according to market research firm IMS Health. Pfizer’s Lipitor, the leader of the class, is the top-selling pharmaceutical ever, with $12.7 billion in sales last year. So anything that comes along that’s more effective, even if it grabs only a sliver of this market, is going to generate serious cash flow.

That’s exactly what Genzyme is banking on. “This offers a significant benefit over the standard of care for a seriously ill patient population. We look at this as a significant driver for us in the future,” Butler says.

A clinical trial last year showed that mipomersen could reduce cholesterol by 40 percent more than statins alone, that it can lower patients’ cholesterol counts to a safe level, and that it can be taken in combination with those drugs. Sounds great, but as Butler says, this isn’t really for everybody. The new drug is only meant to be taken by patients at exceptionally high risk of heart attacks and strokes because of their clogged arteries. Plus, since it’s a weekly injectable, it doesn’t have the same kind of convenience for the masses as a daily pill like Lipitor. (The drug also is designed to work differently than anything on the market. It’s a targeted drug that reduces the production of apoB-100, a protein that’s essential for synthesizing and transporting LDL “bad” cholesterol in the blood.)

“This is not a product that will compete with statins, it’s for patients who aren’t adequately controlled with those drugs,” Butler says.

Mipomersen isn’t scheduled to reach the desk of FDA reviewers until the second half of 2010, so a lot of work still needs to be done to prove it’s ready for the market. Genzyme’s first item on its to-do list is to show that mipomersen works for patients with an extremely rare genetic disorder called homozygous familial hypercholesterolemia that makes it so people can’t properly control cholesterol in the blood. The disorder means that patients have two faulty copies of a gene that controls cholesterol levels, which puts even very young children at risk of a heart attack or stroke, Butler says. About 300 patients, one in a million people in the U.S., have this disorder, and Genzyme expects to be able to ask the FDA for clearance to sell the drug in the second half of 2010 if this trial pans out, Butler says.

That targeting of a small patient population is typical Genzyme. But here’s where the part about thinking bigger enters the picture: …Next Page »

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Cambridge, MA-based Genzyme (NASDAQ: GENZ) and its partner, Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS), said today they have started a pivotal clinical trial for patients with a genetic disorder that causes exceptionally high levels of cholesterol. The study will enroll 100 patients in the U.S. and Canada, to take 200 milligrams of the experimental drug mipomersen or a placebo each week for about six months. Data from the trial, the first of four new studies the companies plan to initiate by year’s end, will be available in 2010.

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The FDA gave MediQuest Therapeutics a boost today. MediQuest, the developer of a treatment for Raynaud’s disease, a painful condition of the hands and feet, said the FDA has agreed to give its drug application an expedited 6-month review since it can treat an unmet medical need. The agency usually takes 10 months to consider an application, particularly if it’s the fourth or fifth in a class of well-known drugs, like statins for lowering cholesterol.

MediQuest, a privately-held company in Bothell, WA, turned in its application to U.S. drug regulators in April. That means the firm may learn as soon as October whether it can make the leap from being solely a developer of new drugs to being a company that also has a product to sell. If approved, the drug would also be the first product specifically for Raynaud’s.

The drug (formerly dubbed Vascana in company statements, now being called MQX-503), is a topical formulation that patients can rub on their hands or feet to prevent or treat the symptoms of a painful Raynaud’s flare-up. About 2.1 million people are estimated to have sought medical treatment for the disease, and about 90 percent are women, MediQuest has said. How many of them may seek out MediQuest’s therapy is the burning question.

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Cambridge, MA-based Genzyme and Isis Pharmaceuticals said today they have modified some of the terms of their partnership to develop Isis’s mipomersen for patients with high cholesterol. The deal, originally announced with a bang in January, still provides $325 million in upfront payments to Carlsbad, CA-based Isis for the antisense RNA-based drug, although it now shifts $50 million more of the drug’s development costs to Isis.

Three months after the original deal was struck, investors in the companies got a bitter pill. The FDA asked Isis (NASDAQ: ISIS) for more study data that is expected to delay the drug’s market application for a year, until 2010. That sent Isis stock plunging 29 percent that day, April 25. Genzyme (NASDAQ: GENZ) will now take the lead on future discussions with regulators, the companies said.

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