Takeda announced June 27 that U.S. regulators had denied approval of its type 2 diabetes alogliptin, a potential blockbuster poised to compete with similar molecules from Merck and the team of Bristol-Myers Squibb and AstraZeneca. The setback will delay alogliptin's launch by at least three years-- and possibly longer-- depending on the additional studies required by regulators.

The negative news increases pressure on Takeda's oncology division, Millennium Pharmaceuticals, to perform. Millennium's first-in-class proteasome inhibitor Velcade (bortezomib) has been one of the few bright spots for Takeda in the past year. After Velcade won approval as a front-line therapy in multiple myeloma, sales of the drug skyrocketed, surpassing the billion dollar mark late in 2008 (¹ Also see "ASH Data Give Millennium’s Velcade A Boost, Raise Bar For Competitors" - Pink Sheet, 15 December, 2008.).

The no from FDA on alogliptin was far from unexpected. In early March, Takeda announced that FDA planned to apply new cardiovascular safety guidelines when reviewing the application of alogliptin, a DPP-IV inhibitor. At that time, the agency indicated the data were not sufficient to satisfy new statistical requirements (² 'The Pink Sheet,' March 9, 2009).

However the delay does create enormous problems for the Japanese pharma. Takeda had been counting on sales of alogliptin to replace revenues lost when its insulin sensitizer juggernaut Actos (pioglitazone) goes generic in 2011. But because the company will have to conduct additional safety studies tied to potential cardiovascular events, it's going to be nearly impossible for Takeda to garner approval and launch alogliptin before Actos' patent expires.

In its year-end earnings call on May 12, a corporate spokesman indicated that Takeda was reviewing the possibility of pushing for a six-month extension on Actos' exclusivity period. However such a development also seems unlikely to transpire. "We are doing our best," the spokesperson said.

In addition to Actos, Takeda also faces the near-term patent expiry of its proton-pump inhibitor Prevacid (lansoprazole) for gastroesophageal reflux disease. In 2008, the PPI was Takeda's second highest-selling drug, generating $3.1 billion in the US alone.

Increased pressure on oncology division

Despite the setback associated with alogliptin, Takeda has earned positive answers from US regulators on two other drugs in recent months. In February, the FDA approved a delayed release PPI called Kapidex (dexlansoprazole), which the Japanese pharma is positioning as a successor to Prevacid (³ Also see "PPI Market Snapshot: Kapidex Joins The Party Fashionably Late" - Pink Sheet, 9 February, 2009.).

Also in February, Takeda's gout medicine Uloric (febuxostat) received a thumbs' up from the agency. Both drugs launched in March, but there is little clarity about the uptake of either in the marketplace. Moreover, revenues from neither medicine are expected to be sufficient to make up for the losses associated with either Prevacid or Actos (⁴ Also see "Takeda Positions Uloric To Gout Patients In Need Of Better Control" - Pink Sheet, 23 February, 2009.).

With alogliptin significantly delayed, Takeda will be relying even more heavily than it already was on Millennium for its continued revenue growth. In April 2008, in a deal that was widely criticized by analysts, Takeda paid $8.8 billion primarily to acquire that group's blockbuster cancer drug Velcade (⁵ Also see "Takeda Reaffirms Oncology Goals With $8.8 Billion Millennium Acquisition" - Pink Sheet, 10 April, 2008.).

In mid-May, Millennium celebrated its one year anniversary as a Takeda company, an event made sweeter because the biotech's senior leadership has remained in place. This is in sharp contrast to other recent acquisitions, including AstraZeneca's buy-out of MedImmune and Roche's purchase of Genentech, which has already resulted in the departure of two key executives, Susan Desmond-Hellman and David Schenkein (⁶ Also see "Genentech Exec Heads East To Take The Reins Of Cancer-Focused Start-up Agios" - Pink Sheet, 27 May, 2009.).

Millennium has already benefited mightily from the deeper pockets of Takeda. The Japanese pharma has doubled Millennium's research budget, allowing the biotech to increase its pipeline from five clinical stage programs to 14 in the intervening months. It has also poured additional resources into marketing Velcade, increasing the number of sales reps supporting the product (⁷ Also see "After Combining Assets, Takeda/Millennium Outline Oncology Strategy" - Pink Sheet, 27 March, 2009.).

"There has been a quantum change in resourcing that is quite remarkable," says Deborah Dunsire, Millennium's CEO.

In an effort to maintain the cultural integrity of Millennium, Takeda has opted to run the group as a stand-alone unit within the parent pharmaceutical company, with senior execs reporting not through its U.S. unit, Takeda Pharmaceuticals North America, but directly to the company's CEO, Yasuchika Hasegawa. That level of autonomy speaks volumes about Hasegawa's faith in Millennium's management, especially Dunsire.

But Millennium will likely have to demonstrate continued success if it wants to retain its special stand-alone status within the Takeda family. The pressure to do more with Velcade is enormous even as a competing molecule with a potentially better side-effect profile from the biotech firm Proteolix winds its way through clinical trials (⁸ Also see "Carfilzomib And Pomalidomide Pass Phase II" - Pink Sheet, 11 December, 2008.).

Late last week, Millennium suffered a minor setback tied to Velcade. The FDA issued a warning letter saying promotional material in the guise of a reminder ad overstated the medicine's effectiveness while skipping over the side-effects (⁹ Also see "Velcade Double Entendre Raises Red Flags At FDA Over Reminder Ads" - Pink Sheet, 24 June, 2009.).

Beyond Velcade, Millennium will need to push forward on the development of MLN-0002, an antibody for ulcerative colitis and Crohn's disease that is currently in pivotal trials. Millennium will also need to work hard to see a smooth launch of motesanib, an oral, pan-VEGF inhibitor being developed in conjunction with Amgen for the treatment of non-small cell lung cancer.

Takeda purchased world-wide rights to motesanib in 2008 as part of a monster two-part deal that also gave the pharmaceutical company Japanese rights to Vectibix (panitumumab) (¹⁰ Also see "Takeda Makes $1 Billion Move For Amgen Development Rights" - Pink Sheet, 4 February, 2008.). In keeping with Millennium's billing as Takeda's oncology franchise, the biotech is leading the commercialization efforts associated with motesanib.

Amgen and Millennium had been hoping to position the medicine as superior to Genentech's Avastin (bevacizumab), currently the only approved treatment for NSCLC. But executives at both companies will need to work hard to allay potential safety concerns after the medicine showed an increased risk of severe bleeding in a certain patient subpopulation. Phase III trials of the drug were halted in late 2008 and allowed to resume in February but the medicine's use is limited to patients with non-squamous types of tumors, who account for only two-thirds of the total NSCLC population.

Dunsire is aware that her unit must perform in order to maintain its autonomy.

"Millennium's autonomy is only worth Takeda's while as long as they continue to believe-- and we continue to demonstrate-- that results can be delivered. The essential ingredients for success are mutual respect and results," she said in a recent interview.

-Ellen Foster Licking (e.licking@elsevier.com)

Takeda's Alogliptin Suffers Major Setback, Delaying Drug Launch Until 2012 Or Later

More from Archive

More from Pink Sheet