Big Bets, Bold Steps

Ken Keller, CEO and president of Daiichi Sankyo’s US business and head of its global oncology unit

Sometimes all it takes to propel a person to a meaningful career—and one’s destined calling—is the promise or sway of the simple things. For longtime biopharmaceutical industry leader Ken Keller, it was the allure of a company car. Fate, of course, has many variables, but as Keller acknowledges, the prospect of cooler wheels upon graduating from St. John’s University with a business and finance degree may very well have been the driving force in setting his professional trajectory—and his life today as he knows it.

“I had two job offers—one to sell tax services for ADP and one to sell antibiotics for Beecham Pharmaceuticals,” Keller tells Pharmaceutical Executive. “I never knew that pharmaceutical sales existed. I didn’t have anyone in my family who was in medicine. But Beecham offered me a company car, and at that time I was driving my family’s station wagon with wood on the side. So I was all in.”

The Long Island, NY, native has kept his chips in play ever since. Keller notably went on to spend 20-plus years at Amgen during the boom of biotech and, this year, is celebrating 10 years as president and CEO of Daiichi Sankyo, Inc., and global head of the Japan-based company’s oncology business—splitting his time between the bustling metropolis of Greater Tokyo, and, more often, the quieter confines of his Basking Ridge, New Jersey, home base. Keller’s journey so far has been marked by scientific breakthroughs, including the landmark approval of antibody-drug conjugate (ADC) Enhertu; ambitious strategic pivots; and personal growth. As he reflects on his decade-long tenure with Daiichi Sankyo and an eventful path preceding, the executive opens up about the trials, triumphs, and lessons that have defined his leadership and the innovative strides the Japanese pharma giant, known for its tradition and legacy in cardiovascular disease, has made in reinventing itself on the oncology stage.

A NATURAL PROGRESSION

Car options aside, Keller, heeding some parental wisdom, knew the sales setting was where he wanted to cut his teeth in the business world. “My dad was an accountant and he would always say, ‘those salespeople—everybody listens to them, they bring in the money. Be a salesperson.’”

After his stint as a sales representative at then-Beecham (today, part of GSK), Keller joined Amgen in 1992, starting out as a sales rep. He was one of 30 people in the organization’s first sales training class, with the company fresh off recent approvals of its first two products, Epogen (epoetin alfa) and Neupogen (filgrastim). From there, he ascended to various positions of increasing responsibility in sales leadership, marketing, and global product management.

With Amgen in “super growth mode,” as Keller puts it, opportunities to advance and stand out at the California-based biotech seemed endless. He recalls a unique influx at the time of “brilliant, unbelievable kinds of people,” working with him on the marketing side in particular. “They were from the best schools in the country, and they all had MBAs. I didn’t really feel like I belonged there that much,” says Keller, who, years later, in 1999, would get his own MBA from Loyola Marymount University. “But I had something they perhaps didn’t. I was the marketing guy who knew customers, who carried a bag—and that was a badge of honor. I’ve always tried to leverage that. Even today, I tell people the most important thing you can do throughout your career is develop that Rolodex of people and customers.”

Cultivating that “customer connectivity” likely helped fuel Keller’s love affair with oncology, which, he says, began to solidify with the launch of Neupogen in the early 1990s. The drug was originally cleared to treat cancer patients receiving myelosuppressive chemotherapy and, subsequently, was approved for several oncology indications as well as severe chronic neutropenia. Neupogen’s success in stimulating the growth of white blood cells—countering the normal cell-killing effects of chemotherapy that can trigger infection, halt treatment, and hasten the potential return of disease, resonated early with Keller.

“It really transformed oncology,” he says. “There is something that when you talk to an oncologist and you bring them something new, something that gets them excited that they can bring their patients, that feeling—if you’ve done that once—you try to recapture it again and again and again. That’s really what got me addicted to oncology.”

In 2002, Keller was named VP of oncology at Amgen, heading up marketing for its cancer portfolio, including the launch of blockbusters Neulasta and Aranesp and later Vectibix, its drug for colorectal cancer. Keller’s next role would take him overseas. In 2005, he moved his family from the US west coast to the UK and Ireland for three years, serving as Amgen’s managing director in both regions. Rounding out Keller’s 21-year run at the biotech power were two years apiece as VP and general manager of inflammation and bone health, respectively (the latter shortly after the launch of Amgen’s Prolia, or denosumab, for postmenopausal osteoporosis).

“I’ve worked in nephrology, I’ve worked in bone health, and we’ve launched some really game-changing drugs there—but the feeling of going into an oncologist’s office, and having a nurse grab you and say, ‘Ken, I’ve got to tell you what happened. We just gave this patient Enhertu, and, wow.’ You don’t get that a lot,” says Keller, alluding to his current role at Daiichi Sankyo and the drug that would become the central thread in his tenure so far.

BUILDING FROM SCRATCH

Following a two-year stint as chief operating officer at Spectrum Pharmaceuticals, Keller was recruited by Daiichi Sankyo’s global arm to shepherd a seemingly monumental task: help turn the more than 100-year-old cardiovascular mainstay into a world-class leader in oncology. He accepted and, at age 51, in March 2014, Keller “was employee No. 1 in the oncology business unit,” he notes. “Now we have over 2,000 people in 55 countries.”

The growth in between can be attributed to many factors, including, of course, strong and aggressive hiring, and attracting the right mix of talent, particularly during the COVID-19 pandemic, which, Keller says, “forced me to hire people from everywhere.” He tapped former colleagues and other top oncology minds from the West Coast biotech scene, and also brought in people from Europe and Tokyo. He credits creating an inclusive environment and focus on work-life balance as factors as well. But perhaps at the heart of the growth was a rare mix of resolve, risk-taking, and seizing on a perfect storm that was occurring in ADC scientific and treatment innovation. “We were working on some different oncology products back then. Some worked, some didn’t,” says Keller. “But none of them were game-changing like these ADCs have become. Sometimes it’s good to get lucky, too.”

The first wave of ADCs, or so-called “smart” chemotherapy that target cancer cells directly (treatments consist of a monoclonal antibody, a chemical linker, and a cytotoxic drug, or “payload”) was ushered in with the 2000 FDA approval of Pfizer’s Mylotarg (gemtuzumab ozogamicin) for adults with acute myeloid leukemia. Other early ADCs targeted blood cancers as well, but researchers sought to develop these treatments to also combat HER2 overexpression, a hallmark of cancer onset and recurrence, particularly in breast cancer. In 2013, Roche’s second-generation ADC, Kadcyla, which combines trastuzumab (the active ingredient in Herceptin) and the cytotoxic agent emtansine, was approved in the US for patients with HER2-positive, metastatic breast cancer. Pursuits in ADCs since have focused on boosting response rates (tumor shrinkage) and progression-free survival by introducing novel payloads and new targets aimed at addressing resistance to HER2-positive standard of care and similar treatments.

Enter Enhertu, originally called DS-8201, a drug described as a tumor-selective cleavable linker that combines trastuzumab and a chemotherapy agent known as deruxtecan (DXd).

“Our scientists in Tokyo basically re-engineered and created a brand new technology,” says Keller. “Our payload is highly potent and the key is it actually diffuses outside of the tumor cell and goes into the tumor microenvironment to exert its cytotoxicity. That allows the payload to stay on the antibody and stay solid through the bloodstream.”

Invented with an eight-to-one cytotoxic drug-to-antibody ratio, according to Keller, allowing additional payloads to be placed, Enhertu’s potential use with various monoclonal antibodies appeared vast. But such promise—and the overall revolution in ADCs that was emerging at the time—was slow at first to garner substantial interest in the research community.

THE TURNING POINT

Those memories still fresh, Keller, with a mix of pride and emotion, is quick to cite the moment—or connected moments—that best encapsulate the Enhertu story, and his journey as CEO. The first occurred at the June 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, where Daiichi Sankyo was presenting Phase I clinical trial data for Enhertu. Despite being a new approach, the drug was perhaps swept up in the wider sentiment at the time of ADCs as largely passé treatments in recent years, Keller says.

“It was the last day of ASCO and it was the last session in the afternoon; that meeting room was completely empty,” he tells Pharm Exec. “We basically presented that data to ourselves. ... Nobody cared.”

The data was from a trial of 50 patients with metastatic breast cancer who had failed up to six lines of therapy. “They had lost all hope,” says Keller. “They were in very, very bad shape.” The results demonstrated a nearly 50% overall response rate to Enhertu in one of the arms, along with a significant duration of response.

“In the very beginning, before we showed that data and when we were doing those initial studies, it was difficult to get investigators and [key opinion leaders] to want to run our studies. Because they didn’t believe,” recalls Keller. “Once we showed that data in those patients that were heavily pretreated, everyone’s eyes opened up and everything changed. ... Data is the lifeblood of oncology.”

Fast forward to December 2019, when Enhertu would gain an accelerated approval by FDA to treat HER2-positive breast cancer in adults with unresectable or metastatic HER2-positive breast cancer who had received two or more prior anti-HER2-based regimens in the metastatic setting (it was cleared based on pivotal Phase II trial results; the drug has boxed warnings for interstitial lung disease/pneumonitis and embryo-fetal toxicity.)

Earlier in 2019, Daiichi Sankyo and AstraZeneca struck a global partnership to jointly develop and commercialize Enhertu (except in Japan), and in January 2021, the drug was cleared in the US for gastric cancer in patients previously treating with Herceptin.

All significant strides, but Keller cites the 2022 ASCO meeting as the ultimate coming out party. Now booked for the plenary session, with a standing-room only crowd, the companies presented late-stage clinical data for Enhertu in HER2-low metastatic breast cancer (50% to 60% of breast cancer cases are classified as HER2-low), a new classification at the time where no approved treatments existed. Enhertu, according to the results, reduced the risk of disease progression or death by 50% versus chemotherapy.

“The presentation ended and it erupted into a standing ovation,” remembers Keller. “It wasn’t just potentially changing the standard of care, it was actually transforming how you treat breast cancer. The HER2-low group is twice as big as the HER2-positive group, so we expanded the number of women that could be helped by more than twofold.”

Given a breakthrough therapy designation for the indication, Enhertu was approved by the FDA in August 2022 as the first HER2-directed drug for patients with HER2-low metastatic breast cancer. In all, Enhertu has been cleared in five indications, including previously treated HER2-mutant metastatic non-small cell lung cancer and most recently, in April 2024, as the first tumor-agnostic HER2-directed therapy and ADC for previously treated patients with advanced solid tumors. The drug is projected to top $9 billion in combined sales by 2028, according to Evaluate Ltd consensus forecasts. It generated $2.74 billion in revenue for Daiichi Sankyo in 2023, more than doubling its total from the previous year.

By 2028, Evaluate predicts the ADC category—today one of the hottest areas for M&A and licensing deals—will be worth almost $30 billion (including pipeline drugs with sales forecasts). Daiichi Sankyo is projected to lead the pack with close to $10 billion in combined ADC sales from Enhertu and current Phase III hopeful datopotamab deruxtecan (Dato-DXd), also in co-development with AstraZeneca. Another Big Pharma alliance could boost future prospects as well. In October 2023, Merck & Co. inked a partnership agreement with Daiichi Sankyo for a share of three Daiichi Sankyo ADC candidates, with Merck paying $4 billion upfront and potentially up to $22 billion.

“In four years, we believe we’re going to have five ADCs on the market; those will have over 20 indications in over a dozen different tumor types,” says Keller. “I see a tremendous wave of excitement for ADCs, with lots of companies working on new versions of drugs with different payloads and different linkers. I really do believe that in 10 years, chemotherapy by itself will probably be very rarely used. Most of it will be displaced by ADCs across the board.”

CULTURE AND COURAGE

To go from zero revenue in oncology in 2019 to being a potential top-10 company in the field by 2026 (if projected sales/approvals pan out), it’s not, of course, just strictly the science—or the magic of timing and innovation—that must all come together cohesively.

The ability of an organization to transform and adapt culturally, starting at the top, is a major catalyst as well. In Daiichi Sankyo’s case, Keller credits the “learning culture” championed by current global CEO Sunao Manabe and Chief Operations Officer Hiroyuki Okuzawa, both with careers at the company spanning decades, in helping to establish a mission-driven mindset in oncology. Counter to the common perception of traditional Japanese culture as being risk averse, Daiichi Sankyo’s executive committee, according to Keller, has embraced the often failure-fraught nature of cancer drug development. Today, incremental treatment gains, most agree, won’t cut it—making every decision to “go or no-go” critical.

“They said, look, if we really want to become a global oncology leader, it’s got to start in the C-suite. And we’ve got to be bold and be willing to make mistakes,” he tells Pharm Exec. “That may not seem like a big deal for an American company. It’s a big deal for a Japanese company. So I give them all the credit.”

Keller, a father of three, and grandfather to three, who this Spring, during cherry blossom season, brought his whole family to Tokyo for the first time, is used to such displays of the larger group’s commitment. One he fondly recalls in particular is when Manabe’s predecessor as CEO, George Nakayama, signed off on investing “hundreds of millions of dollars” in manufacturing for Enhertu and ADC production based on that 50-patient Phase I data presented at ASCO, and years before commercial launch. For an organization largely focused on designing small-molecule pills, taking the leap into the world of complex biologics was quite the statement.

“That took amazing guts to do that on 50 patients. In oncology, to really develop drugs like this, you’ve got to make those kinds of bets,” says Keller. “Their word means everything.”