Stanley Crooke on finally making sense out of antisense

Ask anyone to describe Stanley Crooke, CEO of Ionis Pharmaceuticals, and a single word comes up again and again: intense. Friends and adversaries alike say he operates at an intellectual pace, as both a scientist and a leader, that makes him something of a force of nature. Keep up, or be swept aside.

It took a force of nature to tunnel through the mountain of challenges that defined antisense oligonucleotides, the technology to which Crooke has devoted his career.

In 1989, Crooke set out to build a company that would make drugs out of antisense oligonucleotides: short, single-stranded RNAs that bind to messenger RNA to control protein production. Since then, the technology—and sometimes Crooke himself—has been the subject of withering criticism and downright dismissal. During the darkest years, both the science and the man inspired polar reactions: love or hate, with little in between.

Today, the controversy has faded. The first commercially viable and therapeutically impactful antisense oligonucleotide, the spinal muscular atrophy treatment Spinraza, is on the market. Scientists and investors alike have embraced the idea that the technology might be an answer for some devastating and often intractable neurodegenerative diseases. Many well-funded biotech companies have emerged to explore new ways of using oligos.

And Ionis itself is on the cusp of a major change. With the company on the road to profitability and boasting a healthy pipeline of drugs, Crooke is turning over the reins of the company he built.

Through conversations with Crooke—all fueled by one of his few vices, the retro diet soda Tab—and interviews with former colleagues, contemporaries, and self-described adversaries, a picture emerges of the role he played in bringing oligonucleotide therapeutics to life.

Early years

Crooke’s contemporaries often describe him as one of the smartest people they know. He has an exhaustive knowledge on topics as diverse as pharmacology and poetry. “When he walks in the room, everyone’s thinking gets crisper,” says Brett Monia, Ionis’ chief operating officer, who will become CEO when Crooke retires at the end of the year.

Emblematic of Crooke’s insatiable curiosity is the lab he maintained through his tenure as CEO of Ionis. His unusually intimate involvement with the science leads many company watchers to regard him as Ionis’s de facto chief scientific officer, a position that the firm otherwise never filled. In the comfort zone of his lab, Crooke explores some of the still-unanswered questions about the technology—basic research that has led to more than 60 journal articles in the past decade alone.

But it was never a given that his expansive mind would reach its full potential. Crooke grew up in poverty in Indianapolis, raised sometimes by his grandmother, sometimes by his mother and stepfather. He describes his childhood as rough and says he was constantly in trouble.

Crooke was the first in his family to finish even high school. He went on to college, though with little direction. He was considering law school when a college administrator suggested he look into graduate school. Crooke still marvels that Baylor College of Medicine accepted him into its pharmacology MD-PhD program.

It was at Baylor that Crooke met his most significant mentor, biochemist Harris Busch, who served as his graduate adviser. Crooke’s tough childhood prepared him to connect with Busch, who was an exacting leader with a volatile temper that terrified almost every other student. “I wasn’t afraid of anybody,” Crooke recalls.

Rather, Crooke thrived under Busch’s direction and came to regard his adviser and Busch’s wife as family. Inside Busch’s lab, Crooke discovered his joy for science and his lifelong passion for RNA.

He also learned a lot about himself. “It’s fair to say that Harris was intense, and so was I,” Crooke says. “He helped me to focus my intensity on things that would matter to me for the rest of my life. And he also helped me understand my weaknesses through his weaknesses.”

While most researchers slowly work their way up the corporate ladder, Crooke quickly reached the top rung. After helping build oncology research at Bristol Laboratories, he was hired to lead R&D at SmithKline, which through a series of mergers would become today’s GlaxoSmithKline.

He arrived in Philadelphia in 1980, a time when SmithKline was enjoying the early spoils of what would become the industry’s first blockbuster drug, the ulcer treatment Tagamet. His mandate was to help build a research engine that could produce more big sellers.

“Fair to say that Stan and I were viewed as disrupters,” says George Poste, a professor at Arizona State University who worked alongside Crooke at SmithKline in the 1980s. They introduced scientific rigor to the research group, starting with a thorough investigation of existing programs. Many in the company’s top ranks wondered “what on earth they had unleashed on the organization,” Poste recalls.

“He was an extremely intense analyst of people’s capabilities and their knowledge, but he was unswervingly fair and an excellent mentor,” Poste says of Crooke. “But you didn’t go to meetings unprepared. And the one thing you never did was bullshit him.”

While at SmithKline, Crooke became convinced the drug industry’s model was broken. His observation, one that would shape the next 30 years of his career, was that tethering research to a commercial operation was harmful to innovation. To develop and market their drugs, companies “built this enormous infrastructure and it was a tremendous ballast. Just dead weight,” he says.

He advocated a leaner organization that would focus on innovation and let a partner company take on selling whatever drugs came out of its efforts. To test the model, he needed a technology that could generate a steady pipeline of therapies. A lot of new ideas were floating around at the time—gene therapy, combinatorial chemistry, lipid-based therapeutics. But after hearing a lecture at SmithKline by two pioneers, Crooke was hooked on antisense.

Cultivating a field

In 1989, Crooke formally opened Isis Pharmaceuticals, which he later renamed Ionis Pharmaceuticals. Around the same time, a trio of competitors—Gilead Sciences, Genta, and Hybridon (now known as Idera Pharmaceuticals)—emerged to try to turn oligonucleotides into drugs. The notion that one could control protein function by stringing together the right set of nucleic acids was tantalizing.

Art Krieg, who has spent his career working on antisense, was a postdoctoral researcher at the US National Institutes of Health and recalls “this incredible optimism and excitement—one might say euphoria—at the time that this was rational drug design” for the most challenging targets and diseases. “The idea is it was going to be God’s gift to drug development,” says Krieg, who is now CSO of Checkmate Pharmaceuticals.

That euphoria, stoked in no small part by Crooke, led to a pact with Ciba-Geigy worth $30 million, forged while Ionis was still operating out of makeshift labs. Although the sum seems modest in today’s ebullient biotech environment, it was record setting at the time.

But while the concept was simple—short strands of oligonucleotides could turn up or off the production of specific proteins—the technology was far from ready for prime time.

“Very few people actually had a grip on how difficult it would be to make modified oligonucleotides” that could act on a protein target without degrading or hitting myriad other targets, says Karl-Heinz Altmann, who led chemistry at Ciba-Geigy during the Ionis collaboration. Altmann, who is now a professor at the Swiss Federal Institute of Technology (ETH), Zurich, recalls Ciba-Geigy and Ionis chemists trying “so many modifications” to overcome the challenges.

Ciba abandoned the partnership after merging with Sandoz to form Novartis. But Crooke says it was critical to advancing oligonucleotide chemistry. It also was the first in a series of deals with big biotech and pharmaceutical firms that allowed Ionis to stay afloat during the toughest years.

And the tough years soon arrived. By the early 1990s, the sentiment around antisense had soured. Academic research was being discredited: papers in high-impact publications that described using antisense to understand the function of specific genes had, among other things, misinterpreted off-target effects as antisense effects. “There was a very severe backlash when people realized that a lot of those early papers were wrong,” Checkmate’s Krieg says.

The impact on academic science was lasting. University researchers found it increasingly difficult to get grants to work on the technology. Many turned their attention elsewhere, particularly after the discovery of RNA interference, which uses double-stranded RNA to control protein production.

By the mid-1990s, articles and editorials asked, “Does antisense make sense?” and “Does antisense even exist?” Crooke recalls a biting refrain at the time: “Antisense is nonsense.”

In 1998, Gilead abandoned the field, according to Crooke, announcing that antisense doesn’t work. It was an edict that to this day he seems to take personally.

“No one in the world believed that antisense worked,” says Arthur Levin, who was on the Ionis leadership team from 1995 to 2007 and is now executive vice president of R&D at Avidity Biosciences.

People questioned the basic tenets of the technology: Could these simple strands of nucleic acids be specific to their targets? How did they even work?

Beyond the mechanistic worries, scientists had more mundane concerns. Even though chemists had spent years tweaking the chemical backbones of oligonucleotides, they still didn’t last long in the body. People weren’t convinced they could get inside cells, and at the time they were extraordinarily expensive to make.

The doubters included the regulators. Levin recalls going before a US Food and Drug Administration panel in 1998 to ask for approval for the company’s first drug, Vitravene, a treatment for a rare eye disease that affects mainly people with HIV. “I had an FDA reviewer in a minuted meeting say, ‘I’m wasting my time here because everybody knows that antisense doesn’t work.’ That was the attitude we were fighting in those days.”

Crooke personally came under fire for overhyping antisense, pushing it into the clinic too soon, and minimizing its limitations. Contemporaries are careful how they phrase assessments of Crooke’s public statements during that period, but the implication is that he didn’t always give investors or the public an honest view of the safety and delivery problems associated with the technology.

Crooke disagrees. The job of a CEO is to tell “the best possible truth,” he says. “If you don’t commit to telling the truth about your disappointments and failures as best you can and commit to saying you can’t do it if you get to the place you can’t, then you’re just a huckster. You’re a flimflam.”

Taken in sum, the negative attitude about antisense strongly affected Ionis’s internal culture. Rejected by the outside world, the team responded by hunkering down together.

“The science we did was dismissed, which is just a catastrophic, awful feeling for a scientist,” Crooke recalls. “We couldn’t get our papers published in good journals because we had ‘antisense’ in the title. Many investors were very critical and didn’t believe that we had made progress and that there was evidence that antisense was working. And so we were all very defensive.”

By the early 2000s, when Ionis’s second-generation antisense drugs had made their way to the clinic, Crooke came to accept that his company was going to survive. It had more clinical disappointments to live through—notably, a lung cancer treatment and a Crohn’s disease therapy that both failed in Phase III trials—but he no longer worried about whether antisense would become a viable therapeutic platform.

It was at that point that Crooke realized he needed to change his company’s culture. Having a common enemy brought the research team together, he says, but “it was clear it was going to become detrimental.” The company needed to start acting like it was here to stay.

Levin remembers that period well. One of his jobs was to review company press releases, and he found himself trying to tone down the language. “You try to take out a little bit of that defensiveness,” Levin says. He’d remind colleagues that the naysayers had faded, “but if you have those scars, sometimes it’s hard to stop.”

Meanwhile, Crooke was also facing down some of the flaws he shared with his Baylor mentor, Busch. He began to understand that people did not always respond kindly to his brusque tone or his impatience when they didn’t instantly respond to new information or concepts.

Crooke may have smoothed some edges, but he is still very tough, says Monia, who did his PhD in the academic lab Crooke ran while at SmithKline and has stuck with him since. “He will challenge you at every turn—every time you bring something forward he’ll challenge you and ask why.” But Monia also says Crooke considers his employees family. “You can have knock-down, drag-out arguments about the science,” he says, “but he’s always got your back.”

Turning points

Throughout Ionis’s difficult stretch, which included painful cuts to R&D after compounds failed and partnerships fizzled, researchers plugged away at the science. By 2008, the firm’s fortunes began to turn. That year, Genzyme paid $325 million for access to Kynamro, a treatment for a rare, inherited form of high cholesterol. In 2013 it became the first systemically delivered antisense oligonucleotide to gain FDA approval. The drug was a commercial flop, but the deal kept Ionis afloat.

The team developing Kynamro was led by Crooke’s wife, Rosanne, a pharmacologist who has been with Ionis since the early days. The significance is not lost on him. “It’s very poetic to me that Rosanne’s program and Rosanne’s drug really were the key thing that, at probably our most difficult moment, allowed us to fund the company,” he says.

After the Kynamro approval, Ionis secured a series of lucrative deals with big pharma and biotech firms. But the lack of a big commercial success meant skepticism continued to shadow oligonucleotides.

Then came Spinraza.

The notion of developing a spinal muscular atrophy (SMA) treatment was appealing but created complex challenges for Crooke and his team. Not only would pursuing SMA involve treating infants, but to effectively manage the disease, any drug would need to safely reach their brains and spinal cords through an injection into the spinal canal.

Frank Bennett, who like Monia did his graduate work under Crooke and joined Ionis at the beginning, championed the project. Those who have worked at the company say Bennett is one of the few people who can go toe to toe with Crooke in a scientific debate and emerge on top. “I find it almost impossible to say no to good experiments,” Crooke concedes.

Still, even with evidence in the lab that the therapy could prompt the body to make the protein missing in kids with SMA, the decision to proceed to human studies was not easy. “We had never dosed a baby. Never dosed a child. Never given anyone intrathecal doses. And we were going into babies who were dying,” Crooke says. “I was terrified.”

During the trial, Crooke gave each infant—known to the company only as a number—a name and would check on them daily. Amazingly, the drug worked: without Spinraza, babies’ motor function declined; with the drug, it improved.

In late 2016, the FDA approved Spinraza, making it the first-ever treatment for SMA. “If I had done nothing in my career but Spinraza, that would be enough,” Crooke says.

Spinraza is also a commercial success for its marketer, Biogen, which sells it for a breathtaking $750,000 for the first year of treatment and $375,000 annually thereafter. In 2018, the drug brought in $1.7 billion, of which Ionis got $237 million. The company is finally shifting away from relying on technology licenses and partnerships to bringing in actual product sales.

Although Spinraza will likely soon face competition from a gene therapy and a small-molecule drug, Ionis’s pipeline is producing other treatments that could keep the firm growing. One is Tegsedi, a rare-disease treatment approved last fall and marketed by an Ionis affiliate, Akcea Therapeutics. And many investors are excited by several other advanced molecules, including a cardiovascular treatment that blocks the production of Apo(a), a protein involved in lipid metabolism.

Meanwhile, after withering in the early 2000s, the oligonucleotide field has again bloomed. Several well-funded biotech companies are pursuing antisense oligos or some spin on them. More generally, RNA has become a white-hot target for drug developers.

The scientific world was astounded last year when Boston Children’s Hospital researcher Timothy Yu showed that, in under a year, he had designed a custom oligonucleotide therapy for a girl with Batten disease. His treatment slowed the progression of the rare, neurodegenerative disease, which otherwise would have killed her.

It is amid this gathering momentum in a field he helped build that Crooke is stepping down as CEO. He’ll maintain a role on the Ionis board and, of course, he’s not giving up his dogged pursuit of basic antisense science.

“The work he does in his lab is not about new targets for antisense or going after this or that pathway,” says Checkmate’s Krieg, who over the years has reviewed papers emerging from Crooke’s lab. “He’s going after the fundamental questions at the heart of this modality”—like the mechanism by which oligonucleotides are taken up in cells. “I think that’s one of the things that epitomizes how Stan thinks about a problem. He’s doing the hard experiments.”

Looking back on his 3 decades at Ionis, Crooke believes he has proved his thesis that an antisense company can efficiently develop a steady stream of new drugs. The explosion of activity around RNA science, oligonucleotides in particular, is gratifying. “I’ve led the core science in antisense all of these years, and for me, 2018 was the most exhilarating year I’ve ever had,” he says. “The science I’m doing right now is the best science of my life.”

Still, Crooke bears the scars of all those years in the trenches. “What I never will understand is all the emotion,” he says. “I expected skepticism, but I never dreamed there would be people rooting against us. That I will never understand, and it hurt me. I mean, OK, we might fail, but my God, wouldn’t you like us to succeed?”