Antisense Arrives

After a two-decade cycle of investor embrace and rejection, partnerships won and lost, failed clinical trials, layoffs, and rebuilds, Isis Pharmaceuticals has gained approval for the first systemically delivered drug in a new class known as antisense. Kynamro, a short RNA segment that treats a rare type of high cholesterol, got the Food & Drug Administration’s nod in late January.

Isis continues to face questions about its technology. But the approval kicks off what one analyst has dubbed the “year of antisense,” in which a stream of data is expected to emerge for drug candidates that work by targeting RNA.

Traditional drugs often target a misbehaving protein. An antisense drug aims at the protein’s source. It is usually a strand of RNA designed to bind to messenger RNA, the molecule responsible for shuttling protein-making instructions from DNA in the nucleus out to the ribosome, the cell’s protein manufacturer. Bound and deactivated, mRNA can’t deliver its message, and the protein doesn’t get constructed.

Isis uses oligonucleotides, or short, single-stranded RNA, to bind to mRNA, but many biotech firms are exploring alternative methods of gene silencing. RNA interference (RNAi), which uses double-stranded RNA to turn off genes, has garnered the most press in recent years; companies are also developing treatments based on microRNA, which regulates genes using small, noncoding RNA.

Gene silencing was initially hyped as breakthrough technology, and most agree that, conceptually, it could impact intractable diseases. But critics wonder why it has taken this long for a systemically delivered drug to reach the market, despite the proliferation of companies developing RNA-targeting drugs.

Kynamro’s approval “is tremendously important for the technology,” says Stanley T. Crooke, Isis’ chief executive officer. “It answers the final question for the field, and that is, ‘Will the FDA approve an antisense drug if you do good-quality trials and demonstrate value?’ And the answer is yes.”

Kynamro treats a rare, inherited disease, called homozygous familial hypercholesterolemia (HoFH), that’s caused by the body’s inability to get rid of low-density lipoprotein (LDL), or “bad,” cholesterol. Only about one of every million people has HoFH, which leads to heart attacks and even death at a young age. Isis’ drug works by blocking the production of apoB-100, a protein involved in making and transporting bad cholesterol. People with HoFH will need to take the drug for life, meaning FDA had to be comfortable with its long-term safety, Crooke says.

John M. Maraganore, CEO of Alnylam Pharmaceuticals, a developer of RNAi-based drugs, says FDA’s careful and science-driven review of the New Drug Application for Kynamro was “an important piece of progress” for all companies developing RNA-targeting therapies.

The next candidates likely to go before the agency are Alnylam’s ALN-TTR02, an RNAi-based treatment for transthyretin gene-mediated amyloidosis that is expected to begin Phase III studies later this year; Sarepta Therapeutics’ antisense drug eteplirsen, currently in Phase II tests for Duchenne muscular dystrophy; and OncoGenex’ custirsen, an antisense drug based on Isis’ technology that is in Phase III studies as a prostate cancer treatment.

Although Kynamro’s approval is a confidence booster for these other companies, industry experts warn against drawing broad conclusions about other RNA-targeting drugs. “Each and every next antisense molecule that Isis and others develop is going to have to succeed or fail on its own,” says Eric Schmidt, a stock analyst at Cowen & Co. who coined the “year of antisense” phrase. “Just because we had the first monoclonal antibody approved 20 years ago doesn’t mean it was easy for others to get to the market.”

Another reality check is that Kynamro has serious limitations. Although the drug is effective at reducing LDL cholesterol, worrisome safety issues—namely a buildup of fat and enzymes in the liver—emerged during deliberation of the FDA advisory panel that convened to consider the drug’s approval. Antisense doubters point to these safety red flags when they question the viability of drugs developed with Isis’ technology. The European Union refused to approve Kynamro.

In addition to serving a very small patient population, Kynamro will go up against Juxtapid, a recently approved HoFH treatment from Aegerion Pharmaceuticals. Even though Genzyme, Isis’ development partner, has priced Kynamro below Juxtapid—$176,000 compared with about $250,000 per year—competition will be fierce.

Although cautious not to overplay the FDA nod, Schmidt says that the approval should still be considered a milestone for the technology. “Few investors should doubt today that if antisense is directed against the right target, and developed for a disease where there are no good therapies, that this technology has a chance.”

Questions about commercial success aside, no one can deny that RNA-targeted therapeutics have come a long way. Today, more than 50 clinical trials for drug candidates that use some form of gene silencing are ongoing, notes Kleanthis G. Xanthopoulos, CEO of Regulus Therapeutics, a biotech firm formed in 2007 by Isis and Alnylam to develop microRNA-based therapeutics.

Everyone can also agree that Isis has done most of the grunt work to enable the current pipeline of RNA-targeting medicines. The California-based firm has slogged through many challenges, both scientific and strategic, and weathered years when investors lost faith in the technology.

When Isis formed in 1989, the oligo­nucleotides being explored as drugs sported a phosphodiester backbone, an architecture with a fatal flaw: Enzymes in the body could easily recognize the molecules and break them down. For its first-generation compounds, Isis tweaked the backbone by replacing an oxygen with a sulfur. The resulting phosphorothioates were less vulnerable to enzymes and bound to their targets better.

The results of that technological advance were mixed. In 1998, Isis gained approval for Vitravene, a treatment for a serious eye disease affecting people with AIDS. But Vitravene is injected directly into the eye, and efforts to develop other, systemic drugs never came to fruition. Among the failures was Affinitak, a lung cancer drug using the phosphorothioate backbone that in 2003 did not prove effective in a Phase III study.

Isis chemists continued to look for ways to improve the technology. In the mid-1990s, in work that eventually enabled Kynamro, they inserted methoxyethyl groups on the 2' position of the ribose ring of individual nucleotides. That modification led to a 20-fold improvement in potency.

Isis continued to develop the technology in hopes of further improving the potency of antisense drugs. In 2011, the firm unveiled what it calls its generation 2.5 technology, which involves a different modification to the 2' position on ribose, producing another 10- to 20-fold increase in the oligos’ affinity for their target .

Designing a better oligonucleotide was only one leg of Isis’ journey to commercializing a systemically delivered antisense drug. The company also spent years working out the kinks in its manufacturing process to make the technology viable and, eventually, affordable.

In the beginning, synthesis yields for oligonucleotides were miniscule and costs were huge. In 1991, Isis chemists were only able to make milligrams of oligonucleotides at a time. They plugged away at manufacturing and by 2002 had managed to improve yields by 50%; costs had come down by 99%.

Fast-forward another decade and Crooke says an oligonucleotide-based drug now can be made for about $20 per gram at the ton scale. “We think that over time we can decrease the manufacturing costs even more significantly,” he adds. That will bring the production price to well under the cost of making an antibody and not much higher than the cost of a small molecule, Crooke says.

Along with the 25-year learning curve came many peaks and valleys of investor interest in antisense. Isis went public in 1991. At its high, in 2001, the firm’s stock exceeded $25 per share; two years later, it was below $3.00. That volatility persists: Since last September, the firm’s stock has gone from around $14 to $7.00 and back up to $14 again.

Companies with RNA-targeting technology say they are beneficiaries of Isis’ years of ups and downs. “Our technology can benefit from advances made by the companies, like Isis, before us,” Alnylam’s Maraganore acknowledges. If all goes according to plan, Alnylam could have a drug on the market within 13 years of its formation, he points out. Similarly, Regulus’ Xanthopoulos says the firm will put its first two microRNA drugs into human trials in 2014, just seven years after being founded.

Crooke offers his own assessment of Isis’ place in the biotech history books. After more than a century of development, small molecules still take 16 years to go from discovery to market. “In 23 years, we took a blank piece of paper and invented a technology from start to finish,” he says.

Enough data will soon emerge to answer remaining questions about the promise of Isis’ antisense approach. Nine different drug candidates based on the company’s technology will complete Phase II or III trials this year, Crooke notes, and he’s confident the results will put doubting minds to rest. “This is not a one-trick pony,” he says.