Scientists Cracked a Deadly DNA Puzzle. Then Came the Hard Part

August 14, 2018 Updated: August 14, 2018

In 2002, renowned scientist Phillip Sharp co-founded Alnylam Pharmaceuticals Inc. after learning about an intriguing discovery: Researchers had figured out how to “silence” biological messages sent by the genetic code in worms.

Sixteen years and about $2 billion in research spending later, Alnylam has turned the concept, called RNA interference, or RNAi, into a treatment for people with a rare and deadly genetic disease. It’s the first RNAi therapy ever approved, and a small triumph of humanity’s mastery of his own genetics.

It’s also a cautionary tale of a long struggle to transform a scientific breakthrough into a treatment, and a lesson for companies working with today’s most talked-about medical technologies, such as the gene-editing tool Crispr.

“Expect a long haul,” Sharp said in an interview.

When RNAi pioneers Craig Mello and Andrew Fire won the Nobel Prize in 2006, champagne flowed, analysts predicted drugs for cancer and other disorders would rake in billions of dollars in sales, and dozens of companies jumped into the fray. Most of them abandoned their efforts over the following decade.

Alnylam’s therapy Onpattro was approved by the U.S. Food and Drug Administration on Aug. 10. It temporarily blocks, or silences, the messages carried by defective genes that cause a disease called hereditary transthyretin-mediated amyloidosis, or hATTR. Caused by a flawed gene, hATTR amyloidosis affects as many as 50,000 people worldwide.

The FDA’s landmark approval was narrower than many hoped: for now, only a small subset of patients who suffer from nerve damage caused by the disease are qualified to receive Onpattro — about 3,000 in the U.S. But it opens the door to more therapies and has, at long last, validated Alnylam’s years-long effort.

Hot in the Aughts

Like Crispr today, RNAi was the “next big thing” in biotechnology at the beginning of the last decade.

Scientists had long known that turning off flawed genes, thus preventing them from making harmful proteins, could treat disease. Sharp, who co-founded Biogen Inc. in 1978 and in 1993 won a Nobel Prize for studies related to gene splicing, saw RNAi’s potential in making it happen. He wasn’t alone.

“There were hundreds of companies founded to do RNAi and virtually every major pharmaceutical company had a program with hundreds of people involved,” said Judy Lieberman, a Harvard Medical School researcher who is Alnylam’s scientific advisory board.

The decoding of the human genome in 2003 further expanded that potential by providing a starting point for isolating defective genes that RNAi may one day silence.

In a 2007 interview, Alnylam Chief Executive Officer John Maraganore compared RNAi’s approach to fighting a flood. Conventional drugs address damage that’s already been done, like mopping up the floor.

“With RNAi, you can turn off the faucet,” he said.

Trials and Failures

The hard part has been turning off the faucet in people.

Here’s why: DNA, the human’s genetic code, produces RNA, which carries the instructions for making proteins. Patients with hATTR amyloidosis have a defective gene that leads to the production of misfolded proteins that are deposited into the heart and the nerves, among other places. Patients slowly lose sensation in their hands, arms, feet, and legs as the proteins build up. Eventually, the disorder attacks organs, often killing patients within a few years of diagnosis.

The biggest technical hurdle for Onpattro was getting it into the liver cell’s cytoplasm, where RNAi molecules can gum up the production of those proteins. Alnylam tested various approaches, again and again, Sharp said. Most of this technology was developed in-house.

“It took 10 years and $1 billion of investment to crack the initial delivery hurdle,” said Barry Greene, president of Cambridge, Massachusetts-based Alnylam.

Meanwhile, global pharmaceutical companies gave up on their RNAi efforts. Merck & Co. abandoned the field in 2014, seven years after spending $1.1 billion to buy Sirna Therapeutics. Pfizer Inc. let an RNAi partnership with Mirus Bio Corp. end on schedule in 2008. Swiss drugmaker Roche Holding AG discontinued its RNAi research and an alliance with Alnylam in 2010.

Alnylam, no stranger to setbacks, remained committed. (It bought Merck’s Sirna assets for a fraction of what the pharmaceutical giant paid in 2007.) After its first-generation drug, revusiran, was terminated in 2016 because of safety concerns, Alnylam officials were unbowed: “We’ve been punched in the face before, and we’ve come back,” Greene said at the time.

What Now?

It’s a mindset that could serve Alnylam well today as it seeks a broader approval for Onpattro, which may require additional trials.

Onpattro’s early lead in patients with hATTR amyloidosis may not last long. The FDA is slated to decide on a direct rival from Ionis Pharmaceuticals Inc., Tegsedi, early October. Pfizer’s tafamidis, which works via a different mechanism, has been shown to improve survival.

The world of RNAi therapies is expected to expand now that the first medicine has broken through. Onpattro, also known as its chemical name patisiran, didn’t raise any safety concern, and the FDA isn’t requiring any special programs to monitor or reduce risks.

“The approval of patisiran is the start of something big,” said Steven Breazzano, an analyst at Evercore ISI who recommends holding Alnylam’s stock. “While some would have hoped it wouldn’t have taken this long, the reality of brand new therapeutic modalities is the first one for the field is never quick or easy.”