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A Tale of Two Inhibitors

Bristol Myers Squibb’s PD-1 inhibitor drug, Opdivo, is known to many – but did you know that the drug’s origins have one foot in Japan? Around the year 2000, the drug originated from intellectual property related to the PD-1 gene, created by Japanese company Ono Pharmaceutical Industries, in collaboration with scientists at Kyoto University. Subsequently, the US company Medarex initiated full-scale drug development, using its humanized antibody development technology. Ono received approval from Japanese regulatory authorities to use nivolumab to treat unresectable melanoma in July 2014, which was the first regulatory approval of a PD-1 inhibitor anywhere in the world.

Winners and losers

The Japanese origin of Opdivo is of particular importance to Kota Kodama (Associate Professor, Ritsumeikan University), the lead author of a new paper published in Drug Discovery Today that examines the “victory” of Merck Sharp & Dohme’s PD-1 inhibitor Keytruda over Opdivo. The two drugs are very similar and were both approved in 2014 but, despite an initial regulatory and commercial lead, Keytruda’s sales have eclipsed Opdivo’s since 2018.

The goal of pharmaceuticals is not just to get them to the bedside, but to have them used by more people and in more situations to restore their health.

“I wanted to know what caused the first immune checkpoint inhibitor that can be said to have originated in Japan to lose out to a latecomer,” Kodama explains. “In the long term, I wanted to know what kind of development management would lead to the success of follower drugs.”

So how can a drug win in science but lose in business? Like any good thorny conundrum, the problem offers the scholar and the investigator numerous angles of approach.

Defeat and its lessons

Kodama’s angle of analysis was life cycle management (LCM), which he defines as “management that maximizes drug sales at an early stage and keeps them there as long as possible.” Is this where Opdivo’s owners went wrong? Merck, the paper concludes, took better care of Keytruda by spending heavily to boost its pipeline in moves such as the acquisition of biotech companies with particularly useful strengths. The paper also suggests that better focus on collaborations that bring PD-1 inhibitor drugs into clinical trials as part of a combination therapy would improve their commercial development, as would securing a greater number of indication approvals.

Kodama saw his intuitions and hypothesis confirmed in these conclusions, telling us he thinks the paper’s results and recommendations were “predictable.” However, he notes that some questions are still up in the air and that the external environment and even luck are important determinants of success.

In Japan, the barriers between the natural sciences, social sciences, and humanities tend to be very large

But there are other factors that companies such as Ono and BMS can hope to control a little more easily than raw luck. First, there is mindset. Kodama is firm on this. “The goal of pharmaceuticals is not just to get them to the bedside, but to have them used by more people and in more situations to restore their health. Drug development researchers, including me, tend to forget this, and I believe that more emphasis should be placed on the importance of development management and its education.”

Twin drugs, twin disciplines

In the Japanese context, there is also room for improvement – and walls to be knocked down. Kodama explains, “In Japan, the barriers between the natural sciences, social sciences, and humanities tend to be very large. There is little communication between the disciplines. Consequently, the country produces very few people with the combination of scientific and managerial expertise needed to carry out highly successful development management for drugs. We need to create an environment that educates and develops professionals and experts with multiple disciplines under their belts – say, natural science and social science.”

To the question of whether a study of one drug versus another is enough to draw major conclusions, Kodama insists that a retrospective comparison between two companies and their drugs is sufficient for a reasonable level of generalization. He feels quite comfortable in asserting, for example, that active and effective alliances related to the drug right before it is launched will lead to better LCM. However, every paper has its limits, and every study needs a sequel.

“To predict the future,” Kodama muses, “further research is needed.”

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About the Author
Angus Stewart

Associate Editor of The Medicine Maker

Between studying for my English undergrad and Publishing master's degrees I was out in Shanghai, teaching, learning, and getting extremely lost. Now I'm expanding my mind down a rather different rabbit hole: the pharmaceutical industry. Outside of this job I read mountains of fiction and philosophy, and I must say, it's very hard to tell who's sharper: the literati, or the medicine makers.

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