Denali Therapeutics wants to defeat neurodegeneration. And it now has a new weapon in its armoury with the outright purchase of technology from F-Star designed to help large molecules cross the blood-brain barrier – a perennial problem in neuroscience.
Still, the preclinical assets using this approach have a long way to go – the most advanced project is not likely to hit the clinic until 2020, a spokesperson for Denali told EP Vantage. And, with Denali going after some of the usual targets like Bace and Tau in Alzheimer’s, getting into the brain might not be enough to guarantee success (see table below).
The deal follows a partnership between the two companies dating back to August 2016. It is a coup for the UK-based F-Star: not only does it go some way to validating the group’s technology, it provides a cash injection to fund F-Star’s main focus, bispecific antibodies for immuno-oncology.
Denali will pay $24m up front and up to $447m in milestones to acquire F-Star Gamma, one of a group of smaller companies under the F-Star umbrella. F-Star has previously talked up this asset-centric structure, saying this would allow projects to be separated easily from the main group and licensed or sold – an approach that seems to have worked well in the case of Denali (Interview – F-star hopes to shine in bispecific antibody space, February 01, 2017).
F-Star also has partnerships with Abbvie and Merck KGaA covering I-O candidates.
Fcab for Denali
As for Denali, it has made a relatively small bet on technology that has the potential to get drugs into the brain.
The assets it has acquired use the same technology as the rest of F-Star’s pipeline, but employed in a slightly different way.
F-star has developed bispecifics that incorporate a binding site on the constant Fc region of an antibody, resulting in what it calls an Fcab, in addition to separate binding regions at the antibody's usual antigen-binding arms or Fab fragments.
Conventional bispecifics tend to involve two antibody halves merged together, each with a different Fab fragment.
In the case of the neurodegeneration projects bought by Denali, the Fcab is designed to bind to a transporter in the blood-brain barrier (BBB). “That serves as kind of an escalator that brings [the molecule] through the BBB,” F-Star’s chief executive officer, John Haurum, told EP Vantage.
The Fcab can be paired with other molecules, such as antibodies or enzymes, which then act within the brain. Once in the brain, Denali could target “anything” with this approach, Mr Haurum added.
Denali tells EP Vantage that it has four projects in its core portfolio that employ the BBB-crossing technology, which it calls TV, for “transport vehicle”. ATV refers to projects involving antibodies, while ETV refers to those employing enzymes.
|Denali’s BBB-crossing projects|
|ETV:IDS||Iduronate 2-sulfatase||MPS II (Hunter syndrome)|
|ATV:ASYN||Alpha-synuclein||Parkinson's, DLB, MSA|
|ATV:TREM2*||Triggering receptor expressed on myeloid cells 2||Alzheimer's|
|*Partnered with Takeda. DLB=dementia with Lewy bodies. MSA=multiple system atrophy. Source: company website.|
The most advanced of these is ETV:IDS, which is being developed for the rare lysosomal storage disease Hunter syndrome; Denali said yesterday that the project had demonstrated preclinical proof of concept, and the spokesperson added that an IND filing is expected by the end of 2019.
There is a clearer rationale for looking at iduronate 2-sulfatase, an enzyme that is deficient in Hunter syndrome, than some of the targets involved in Denali’s Alzheimer’s projects. The relevance of Bace in particular has been questioned after various recent flops – although Denali might put previous failures down to molecules’ inability to enter the brain.
The two Alzheimer’s candidates listed above are covered by a $150m deal between Denali and Takeda dating from January. Denali is responsible for development up to IND filing, after which the Japanese company can opt in. The Denali spokesperson said that an IND for the first ATV project should happen in 2020.
Denali already has small-molecule candidates in phase I development that do not require the TV technology: two LRRK2 inhibitors for Parkinson’s, and one Rip kinase 1 inhibitor for Alzheimer’s and amyotrophic lateral sclerosis.
The success of the BBB-crossing approach hinges on two things: getting a drug into the brain, and hitting the right target once it is there. Denali seems to believe that it has found a way to achieve the former with F-Star’s Fcabs. The latter might be the tougher challenge.