TOKYO (Reuters) - Takeda Pharmaceutical Co Ltd's 4502.T $64 billion bid for London-listed rare disease specialist Shire Plc SHP.L bolsters its credentials as Japan's most outward facing drugs firm, a mould-breaking image that has been more than a decade in the making.

FILE PHOTO: Takeda Pharmaceutical's signboard is seen on its headquarters building in Tokyo, Japan January 30, 2018. REUTERS/Kim Kyung-Hoon/File Photo

Under chief executive Christophe Weber and his predecessor, Yasuchika Hasegawa, Takeda has cut its exposure to Japan, brought in expertise through overseas acquisitions and thrown open its leadership ranks to foreign talent.

Some investors worry that Takeda, with only $4.3 billion in cash on hand for the Shire deal, may be overreaching.

The company’s shares dropped more than 7 percent on Wednesday after Shire said it was willing to recommend the offer to shareholders, and are down 18 percent since news of Takeda’s interest in a deal became public in late March.

But few argue that Takeda’s management isn’t ready to go global.

Already only 30 percent of the company’s drug sales come from Japan, and 70 percent of its workforce is based overseas. The Shire deal would radically accelerate that shift, adding more than $9 billion in U.S. revenue.

“Takeda has been, is and will continue to be the truly international pharmaceutical company of Japanese origin,” said Philippe Auvaro, Tokyo-based president of rare disease specialist OrphanPacific Inc and a friend of Weber’s.

To get there, the company reshaped its corporate culture, along the way fending off a revolt against Hasegawa, who saw a focus on foreign business as the future.

Takeda declined to make Weber or Hasegawa available for this story. Shire declined to comment.

SHOCK TACTICS

Hasegawa was the architect of Takeda’s shift. He took the company’s reins from Kunio Takeda, the last member of the founding family to run the 237-year-old drugmaker.

Hasegawa was determined to look overseas for growth as well as leadership. His philosophy propelled the company onto its continent-straddling path as it acquired U.S. biotech business Millennium Pharmaceuticals in 2008 and Swiss drugmaker Nycomed in 2011.

His pursuit of foreigners to fill Takeda’s executive ranks cut against the grain of Japan’s insular corporate world.

The surprise decision to appoint Weber - then the company’s chief operating officer - as his successor led to open revolt among some of Takeda’s old guard.

In 2014, more than 100 former executives and investors signed a letter of objection, calling Weber’s appointment a “hijack by so-called foreign capital... something that should never be allowed.”

But Hasegawa was unwavering. Acquisitions were essential if the drugmaker was to rebuild its pipeline as drugs lost patent protection, he told shareholders. Weber was the best choice to take Takeda’s new products out into the world, he said.

In the end, Weber’s appointment sailed through the annual shareholders meeting, with more than 90 percent of the votes in favor.

QUIET REVOLUTIONARY

At first glance, the mild-mannered Weber might not seem the most likely choice to orchestrate the biggest overseas acquisition in Japanese history.

But those who have worked with him praise his ability to convince others of the need for radical change, making him ideal for a company trying to expand globally.

Peter Feldinger, who worked at Nycomed and Takeda before becoming a consultant, said the union of the two companies had stalled until Weber took charge.

“It was complicated to take an inherently old, conservative Japanese organization” and get it to understand the world had changed, he said.

Brought up in the Alpine city of Annecy, the son of two doctors, Weber spent two decades at GlaxoSmithKline GSK.L, including a stint as head of its vaccines unit.

He took over as chief executive in 2015 after joining Takeda a year earlier as chief operating officer.

Hasegawa stayed on as chairman, using his position to act as a “shield” while Weber pushed through unpopular moves, said Tosh Nagate, formerly at Takeda and now chief executive of e-Projection, a company that helps foreign drugmakers expand in Japan. Hasegawa stepped aside into an advisory role last year.

One of the most difficult decisions was to reduce the number of research and development areas. The company also retrenched in two key sites: Boston and Shonan, southwest of Tokyo.

Under Weber, Takeda’s involvement in the Japanese market has continued to wane. The U.S. now accounts for 35 percent of drug sales, but Takeda has promised to keep its headquarters in Japan.

Weber has also been proactive in chasing down cross-border deals, announcing the $5.20 billion purchase of U.S. cancer drug maker Ariad Pharmaceuticals Inc last year and Belgian biotech group TiGenix NV in January as it tries to rebuild its drug pipeline.

While questions remain over whether Takeda overpaid for its past acquisitions, drugs on the market as a result are feeding stronger recent results. [nL4N1PR2AM]

ESCAPE VELOCITY

Acquiring Shire would transform Takeda’s position in rare diseases, gastrointestinal disorders and neuroscience, where Shire is a leader in ADHD drugs.

For now, many of its peers remain highly exposed to Japan, although a shrinking population and annual drug price revisions have encouraged them to consider overseas expansion plans of their own.

Ono Pharmaceutical Co Ltd 4528.T, which co-developed the blockbuster cancer drug Opdivo with Bristol-Myers Squibb Co BMY.N, recently said it was looking to build its own sales network in the U.S. and was considering acquisitions.

Eisai Co Ltd 4523.T favors a different approach. Last month it signed a deal to collaborate with Merck & Co Inc MRK.N to develop and sell its cancer drug Lenvima, both alone and in combination with Merck's immunotherapy product, Keytruda. [nL2N1QP262]

Weber will be under pressure to prove his strategy is the right one - particularly as one of the best-paid executives in Japan. His annual pay is more than 1 billion yen.

“Highly paid and saying he will stay on until 2025, it’s possible he feels that he needs to do something big for his reputation as CEO,” UBS analyst Atsushi Seki said.

Complicating matters is that chief financial officer Costa Saroukos, who had overseen the finances of Takeda’s Europe and Canada businesses, only started in his new role this month.

Takeda’s previous CFO, James Kehoe, quit abruptly in March, citing Japan’s high tax rates and a desire to return to the U.S.