The use of antisense oligonucleotides in biotech drug development took another step forward with the FDA's acceptance of the new drug application (NDA) for Kynamro (mipomersen sodium) filed by Genzyme, a unit of Sanofi SA.

The initial indication for the first-in-class apolipoprotein B (apo B) synthesis inhibitor in the U.S. is the genetic disorder homozygous familial hypercholesterolemia (HoFH), and next in line is the compound's use in severe heterozygous familial hypercholesterolemia (severe HeFH) to further reduce LDL-cholesterol (LDL-C) in patients already on a stable regimen of maximally tolerated lipid-lowering therapies.

Acceptance of the NDA, filed in March, triggered a $25 million milestone payment to Isis Pharmaceuticals Inc., of Carlsbad, Calif., which partnered mipomersen with Cambridge, Mass.-based Genzyme in early 2008 for $150 million in stock, a $175 million license fee and up to $1.575 billion in milestone payments.

If the drug reaches market, Isis is entitled to a share of profits on a sliding scale starting at 30 percent and rising to 50 percent as mipomersen annual revenues reach $2 billion. (See BioWorld Today, Jan. 9, 2008.)

Subject to a standard review, the application will have a PDUFA date of Jan. 29, 2013.

In July, Genzyme submitted a marketing authorization application (MAA) with the European Medicines Agency for marketing approval of Kynamro in both HoFH and severe HeFH, so commercialization in Europe is likely the next step for the drug.

The FDA submission for Kynamro was supported by the largest clinical trial conducted to date in the HoFH patient population. In the randomized, double-blind, placebo-controlled, multicenter trial, significant reductions were observed in all atherogenic lipoproteins evaluated – including LDL-C, apo B and lipoprotein-a (Lp[a]) – in patients receiving Kynamro who already were receiving a regimen of maximally tolerated lipid-lowering therapies, including statins.

Kynamro is designed to reduce LDL-C by preventing the formation of atherogenic lipoproteins, the particles that carry cholesterol through the bloodstream. The second-generation antisense drug blocks the production of apo B, the protein that provides the structural core for atherogenic particles, including LDL and Lp(a).

All told, the drug has been evaluated in more than 800 patients, according to Stanley Crooke, founder, chairman and CEO of Isis.

Crooke and David Meeker, Genzyme's president and CEO, agreed that acceptance of the NDA and MAA represented validation of the antisense drug platform.

"We've proven that this drug can be used effectively and, obviously, with acceptable safety, from our standpoint," Meeker told BioWorld Today.

FH represented an attractive initial target because the disease results in family patterns of premature heart disease, with some individuals suffering heart attacks before age 30. FH patients have inherited abnormalities in the liver cells responsible for clearing LDL particles from the blood.

"It's a life-threatening disease, which is highly underappreciated," Meeker said.

Patients characterized as having severe FH include those who have inherited the disease from both parents (HoFH) and those who have inherited it from one parent in a particularly severe form (severe HeFH). The most severely affected patients have LDL-C levels two to four times higher than recommended levels, even with the use of multiple cholesterol-lowering medications.

With its unique mechanism of action, "[Kynamro] is distinct from all other lipid-lowering drugs out there," Meeker said.

Beyond Kynamro, Genzyme "will continue to look for areas of mutual interest" in potentially exploring additional license agreements with Isis on the antisense technology, Meeker said.

Although the milestone associated with acceptance of the NDA submission is a relatively small one for Isis, it represents a double dose of good news for the company, which anticipates making the transition from a development-stage company to a commercial entity this year.

"Kynamro has worked in the 20-plus clinical trials we've done and shown a beautiful dose-dependent reduction of its target, apo B, and all of the atherogenic lipids that are associated with apo B, " Crooke told BioWorld Today. "The data are overwhelming."

In addition to seeking to expand the indications for Kynamro, Isis is moving 14 second-generation antisense drugs through the development pipeline "to a variety of targets in a variety of organs in a variety of disease states," Crooke said. Potential indications include metabolic, rare and inflammatory diseases, as well as cancer.

In January, the company began dosing patients in a Phase I study of ISIS-SMNRx in spinal muscular atrophy in a potential $299 million pact inked with Biogen Idec Inc., with results expected in early 2013. (See BioWorld Today, Jan. 5, 2012.)

Isis also has a potential $1.5 billion RNA drug discovery alliance with GlaxoSmithKline plc, structured as an option deal. Candidates so far selected for development include ISIS-TTRx in TTR-related amyloidosis, which has completed a Phase I safety study, and ISIS-AATRx, which reduced production of alpha-1 antitrypsin, or AAT, for the treatment of liver disease in patients with the genetic disease alpha-1 antitrypsin deficiency. (See BioWorld Today, April 1, 2010.)

Isis, which plans to continue to develop compounds internally and out-license them "at the right moment," has a raft of additional partners, and discussions have risen "two or three octaves higher" with Kynamro's success in the clinic, Crooke said.

The journey has taken more than 20 years and nearly $3 billion in investment, but "we feel we're very much in the catbird seat," he added.

"Kynamro was the first compelling evidence that second-generation antisense drugs work well in human beings, but now it shares that billing with 13 others that also work very well," Crooke pointed out. "The technology has come of age, and we think we have control of the RNA space for quite a long time."

On Tuesday, shares of Isis (NASDAQ:ISIS), closed at $9.91, up 12 cents.