The confetti is still flying from Eli Lilly’s party celebrating the approval of Alzheimer’s disease therapy donanemab, but the company is yet again facing the harsh reality of the neurodegenerative disease with the failure of an early tau-targeting med.
Lilly Chief Scientific Officer and President, Lilly Research Laboratories Daniel Skovronsky, M.D., Ph.D., said the O-GlcNAcase Inhibitor called LY3372689 failed on the primary endpoint of a phase 2 clinical trial recently. The therapy, which targets the OGA enzyme, did not spur a change in baseline to endpoint time in a rating scale of Alzheimer’s severity in either dose tested.
“While this negative outcome was disappointing, we remain committed to tap as a high conviction target in Alzheimer’s disease and plan to continue studying tau biology,” Skovronsky said, speaking on a second-quarter earnings call Thursday.
The executive said the company is currently reviewing the data for presentation at an upcoming medical conference.
LY3372689 was a key part of Lilly’s next wave of Alzheimer’s efforts. After getting donanemab approved in July, to be marketed as Kisunla, the company was hoping that tau would be the next front in the fight against the memory-robbing disease.
Behind Kisunla, Lilly has remternetug in phase 3 development, which targets amyloid plaques in the brain. Positive allosteric modulator mevidalen is in phase 2 testing. The company also has two undisclosed neurodegeneration medicines in phase 1.
Lilly also trimmed around the edges of other programs after getting some early data on a few candidates.
They include LOXO-783, a highly mutant-selective, brain-penetrant, allosteric small molecule PI3Kα H1047R inhibitor that was acquired as part of the acquisition of Loxo Oncology. The drug was being investigated in a phase 1 study in patients with PIK3CA H1047R-mutant advanced breast cancer and other solid tumors.
Lilly had taken LOXO-783 into the clinic on the basis of preclinical data showing activity without on-target wild-type PI3Kα mediated toxicity.
“We evaluated the ongoing clinical data for the program and compared the molecule to next-generation candidates that we have progressed from our discovery efforts,” Skovronsky said on the call. “We believe our next molecules have greater potential benefits to patients.”
Also on the discard pile is an unnamed NRG4 agonist. Neuregulin 4 acts locally on brown and white adipose tissue and works to protect against obesity-related inflammatory and hypoxic events.
The Big Pharma had halted work on the asset as “the profile is insufficient for further clinical development,” Skovronsky explained.
A GITR antagonist has also been removed from the phase 1 immunology pipeline “due to insufficient efficacy,” Skovronsky said. At the time of publication, Lilly had not confirmed to Fierce whether this was LY3461767, a GITR antagonist that was being evaluated in a phase 1 trial of the drug in patients with chronic heart failure with reduced ejection fraction.
Acadamic researchers have named glucocorticoid-induced tumor necrosis factor receptor (GITR), a co-stimulatory immune checkpoint protein, as playing a pivotal in cardiovascular disease. It’s also been suggested as a potential target to enhance immunotherapy, in particular immune checkpoint inhibitors.