Lexicon Pharmaceuticals’ pursuit of the last word in obesity candidates has attracted Novo Nordisk. The Danish drugmaker is betting $75 million in upfront and near-term milestone payments to secure global rights to a preclinical prospect that paired well with its GLP-1 blockbuster semaglutide in mice.
The small-molecule candidate, LX9851, is designed to increase the feeling of fullness by inhibiting ACSL5. Lexicon targeted the enzyme after finding that knocking out its gene resulted in mice with substantially less body fat but the same lean body mass. The research pointed to ACSL5 inhibition as a way to reduce body fat, cholesterol and triglycerides while preserving muscle—the holy grail in current obesity research.
Novo has identified LX9851 as an asset that can help defend and grow its obesity kingdom. The upfront and near-term payments form part of a total package that could be worth $1 billion, plus royalties, if the deal meets all its development, regulatory and sales milestones, though with the normal caveats that this is still very early stage and has a lot to prove in the clinic.
Lexicon had planned to file to study LX9851 in humans this year, teeing (PDF) it up to enter phase 2 in obesity and start exploring other indications in 2027 and beyond. The deal now makes Novo responsible for the IND filing, as well as for all further development, manufacturing and commercialization.
Novo sealed the deal after Lexicon shared preclinical data on LX9851 in combination with semaglutide, the GLP-1 drug the Danish drugmaker sells as Ozempic and Wegovy for diabetes and obesity, respectively. Lexicon showed mice ate less when taking LX9851 and semaglutide than when on either molecule as a single agent.
As importantly for Lexicon’s positioning of LX9851 in chronic weight management, the studies suggested the ACSL5 inhibitor may help maintain weight loss. When semaglutide was withdrawn, mice regained the weight they had lost, reflecting what happens after people come off the drug. Mice that took LX9851 maintained most of the weight they had lost even after coming off semaglutide.
Craig Granowitz, M.D., Ph.D., Lexicon’s chief medical officer, outlined the opportunities on an earnings call early this month, telling analysts that the drug candidate could work as a monotherapy or combination therapy. The monotherapy opportunity includes use after discontinuation of an injectable or other GLP-1 agonist, knowing “that a vast majority of patients don't remain on therapy for more than a year,” Granowitz said.
Lexicon had three goals for its phase 1 trial. Granowitz wanted to show weight loss in patients is similar to in mice, prove “a clear mechanistic differentiation from the GLP-1 mechanism” and assess tolerability. Lexicon didn’t see anything in the animal models to suggest tolerability will be an issue, Granowitz said, but LX9851’s novel mechanism of action means it is unclear how humans will respond to the molecule.
The company made those preparations for phase 1 while evaluating potential partnership opportunities. Lexicon CEO Mike Exton, Ph.D., said on the earnings call that “there's a number of companies that have not only been interested in this particular asset, but have engaged in the data over the last months.” The company had “been talking to a number of players” about a partnership, Exton said.
Novo fits the profile of the type of partner Lexicon wanted. The company was seeking a partner because it believed the asset would be best served by a drug developer capable of capitalizing on “the breadth of indications” open to the drug candidate, Exton said. Lexicon sees opportunities in metabolic syndrome and metabolic dysfunction-associated steatohepatitis, indications that are in Novo’s wheelhouse.
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