Takeda Pharmaceutical and Denali Therapeutics said today they will partner to develop up to three therapeutic candidates for neurodegenerative diseases, including Alzheimer’s disease, through a collaboration that could generate about $1.2 billion for Denali.

Takeda plans to use Denali’s Antibody Transport Vehicle (ATV) platform for increased exposure of biotherapeutic products, a technology designed to enhance penetration of the blood–brain barrier. Each treatment would be directed to a genetically validated target for neurodegenerative disorders, the companies said.

In a regulatory filing, Denali identified the three programs as two preclinical Alzheimer’s focused programs that have been previously disclosed, ATV:BACE1/Tau and ATV:TREM2, and a third discovery-stage program whose approach and disease have not been disclosed.

BACE1, or β-secretase 1, is an enzyme known to play a key role in the production of amyloid-β, a protein that accumulates in the brains of people with Alzheimer’s years before the onset of clinical symptoms.

Drug developers have long struggled to create successful new drugs for the disease. Only a handful of drug successes have ever won marketing approvals, and those treatments have only slowed progression of symptoms by 6 to 12 months. A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer's drug candidates between 2002 and 2012.

Takeda and Denali have agreed to jointly commercialize products in the U.S. and China, with Takeda holding exclusive commercialization rights in all other markets. The parties will share global profits equally. 

The collaboration is intended to bolster one of Takeda’s three therapeutic areas of focus. The other two are oncology and gastroenterology diseases—the latter area also addressed by Takeda today through its planned €520 million ($632 million) acquisition of TiGenix.

“New Modalities”

“This partnership further exemplifies Takeda’s continued commitment to developing genetically validated therapies for neurodegenerative diseases through an enhanced portfolio comprised of new modalities,” Emiliangelo Ratti, head of the neuroscience therapy area at Takeda, said in a statement.

The collaboration agreement will take effect when the requirements of the Hart–Scott–Rodino Antitrust Improvements Act of 1976 have been satisfied, the companies said.

Denali stands to gain up to $1.173 billion from the collaboration. Once the agreement becomes effective, Takeda has agreed to pay Denali $155 million, to consist of $40 million upfront, a preclinical milestone payment of $5 million, and $110 million to purchase approximately 4.21 million shares of Denali common stock at approximately $26.10 per share.

The $5 million payment is part of a total $75 million in preclinical milestone payments—$25 million per program—that Takeda has agreed to pay Denali under the collaboration.

Takeda has also agreed to pay Denali:

  • A $5 million option fee for each target for which it exercises its option, up to $15 million total.
  • Clinical and regulatory milestone payments totaling $707.5 million if Takeda exercises its option for all three programs.
  • Up to $75 million per biologic product upon achievement of an undisclosed sales-based milestone—an aggregate of $225 million if one biologic product from each program achieves the milestone.

Denali has agreed to be responsible for all development activities and costs prior to Investigational New Drug (IND) filing for each of the three programs, while Takeda has the option to co-develop and co-commercialize each of the three programs.

Should Takeda exercise the option, the companies have agreed to jointly conduct clinical development and share all costs equally. Denali will lead early clinical development activities and Takeda will lead late-stage clinical development activities, the companies added. 

Denali’s partnership with Takeda marks its first collaboration since last month, when it launched an initial public offering that generated $229 million in net proceeds—the largest IPO on a U.S. stock exchange (NASDAQ Global Select Market). 

“We are impressed with Takeda’s commitment to developing treatments for difficult to treat neurodegenerative diseases and look forward to partnering with them to bring medicines to patients,” added Denali CEO Ryan Watts, Ph.D. 

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