Lilly Celebrates Donanemab Approval but Faces Phase 2 Tau-Targeting Drug Failure

Eli Lilly recently celebrated the approval of their Alzheimer’s drug donanemab, known commercially as Kisunla, but the company is now grappling with a setback in another Alzheimer's therapy. The pharmaceutical giant's experimental medication LY3372689, an O-GlcNAcase inhibitor, failed to meet its primary endpoint in a Phase 2 clinical trial. This drug targets the OGA enzyme but did not produce significant changes in Alzheimer's severity in the tested doses, as noted by the company’s Chief Scientific Officer and President of Lilly Research Laboratories, Dr. Daniel Skovronsky.

Despite this disappointment, Skovronsky emphasized Lilly's ongoing commitment to exploring tau biology as a promising target for Alzheimer's treatment. The company intends to present the data from this trial at an upcoming medical conference. Following the approval of donanemab, Lilly had high hopes that targeting tau proteins would be the next significant stride in combating Alzheimer's disease.

In addition to Kisunla, Lilly is also developing another Alzheimer's drug called remternetug, which is currently in Phase 3 trials and targets amyloid plaques in the brain. The company has other promising candidates in the pipeline, including mevidalen, a positive allosteric modulator in Phase 2 testing, and two undisclosed neurodegeneration drugs in Phase 1.

Lilly has also been streamlining its research programs based on early data from some of its candidates. One such drug is LOXO-783, a highly selective, brain-penetrant PI3Kα H1047R inhibitor acquired from Loxo Oncology. This molecule was being tested in a Phase 1 trial for patients with PIK3CA H1047R-mutant advanced breast cancer and other solid tumors. However, after evaluating ongoing clinical data and comparing it to next-generation candidates, Lilly decided to discontinue this program, believing newer molecules have better potential benefits.

Additionally, Lilly has halted the development of an unnamed NRG4 agonist, which acts on brown and white adipose tissue to protect against obesity-related inflammatory and hypoxic events. Skovronsky explained that the drug's profile was insufficient for further clinical development.

Another candidate removed from Lilly’s pipeline is a GITR antagonist, which was being tested in a Phase 1 trial for patients with chronic heart failure with reduced ejection fraction. The company concluded that this drug showed insufficient efficacy. Academic researchers have identified glucocorticoid-induced tumor necrosis factor receptor (GITR) as an essential protein in cardiovascular disease and a potential target for enhancing immunotherapy, particularly immune checkpoint inhibitors.

Eli Lilly's recent developments reflect both progress and challenges in their quest to combat neurodegenerative diseases, particularly Alzheimer's. While the approval of donanemab is a significant milestone, the failure of LY3372689 highlights the complexities of developing effective treatments. Nonetheless, the company remains dedicated to advancing its research and bringing new therapies to market, demonstrating the ever-evolving nature of pharmaceutical innovation.