Tau Modification Drugs Take a Hit with Negative Trial

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2024 - 17th:

While anti-tau antibodies are beginning to look promising (see previous story), small molecules that modify tau proteins haven’t yet fared well in clinical trials. At the 16th Clinical Trials on Alzheimer’s Disease conference, held October 29 to November 3 in Madrid, Eli Lilly’s negative trial was a setback for ceperognastat, the company’s inhibitor of O-linked-β-N-acetylglucosaminidase (O-GlcNAcase, aka OGA).

  • Ceperognastat slowed the rate of brain atrophy and tau accumulation compared to placebo.
  • Alas, cognition declined faster in the high-dose group.  
  • Adverse events suggest ceperognastat may modify other proteins and cause harm elsewhere in the brain or body.

O-GlcNAcase is an enzyme that removes sugars from serine or threonine residues on thousands of nuclear, mitochondrial, and cytoplasmic proteins, including tau (see Zachara et al. chapter in Essentials of Glycobiology, 2022). These moieties seem to compete with phosphorylation at certain sites in tau, stabilizing the protein and making it less prone to form neurofibrillary tangles. In mouse studies, inhibiting OGA with small molecules has led to less hyperphosphorylation and subsequent NFT formation (Mar 2012 news; Mar 2024 news).

Sugar On, Sugar Off. Many mammalian proteins are modified by monosaccharides of O-linked β-N-acetylglucosamine. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove O-GlcNAc, respectively. On some proteins, O-GlcNAc competes with phosphorylation for serine/threonine residues, and some proteins cycle between phosphorylated and glycosylated states. [Courtesy of Essentials of Glycobiology, 2022.]

For its Phase 2 PROSPECT-ALZ study, Lilly tested ceperognastat in 327 people with early symptomatic Alzheimer's, stratifying them into low/medium and high baseline tau groups. They treated both groups with either 0.75 or 3 mg doses or a placebo for 76 weeks.

Taking Out OGA. The rationale behind small-molecule OGA inhibition is that these drugs will decrease tau hyperphosphorylation and aggregation into neurofibrillary tangles (right). [Courtesy of Eli Lilly & Co.]

In his October 30 CTAD presentation, Lilly’s Adam Fleisher showed that ceperognastat missed its secondary outcome of reducing clinical symptoms in either group. On the contrary, the 3 mg group declined significantly faster on almost all cognitive measures compared with placebo. Both dose groups also had more serious adverse events, including cardiac and nervous system disorders and neoplasms. Treatment-related effects such as headaches and cardiac abnormalities were twice as likely to be severe in the high compared to the low-dose group.

Intriguingly, though, the primary outcomes told a different story. The treatment groups lost up to 45 percent less hippocampal volume over the 76-week period than did people on placebo. Moreover, the 3 mg group showed statistically significant slowing of tau accumulation in the temporal lobe, as per flortaucipir PET. Ceperognastat also improved plasma biomarkers, lowering phosphorylated tau217 levels and inflammation signals in the low/medium tau population.

In a statement to Alzforum, Lilly’s corporate communications said the company is continuing to monitor data from an extended safety study that will wrap up in February 2025. “Although the primary endpoint was not met, this study provided learnings with regards to the possibility of discordant outcomes of clinical and biomarker endpoints,” the company wrote. “Future studies, while currently not being planned, might be potentially considered.” Lilly added that it will “continue to explore potential treatments targeting [tau] pathology.”

Adam Boxer, University of California, San Francisco, told Alzforum the results fit with his concerns about small molecules targeting post-translational tau modifications. OGA drugs, he said, “have been around for a long time and so it’s interesting to see definitive results.” While the PROSPECT-ALZ results support the hypothesis that increasing glycosylation reduces tangle formation, the finding that patients did worse bodes ill for its clinical potential, at least as pursued currently.

Likewise, Rakez Kayed, University of Texas Medical Branch, Galveston, was unsurprised the trial result was negative. To his mind, targeting an enzyme that affects thousands of proteins throughout the body is a “nonstarter” due to potential off-target effects. “Even if it worked and met its secondary endpoints, the side effects could be massive,” he said.

OGA’s opposite, the O-GlcNAc transferase enzyme that attaches GlcNAc to protein serine and threonine residues, was spotted in the postsynaptic density of spines of excitatory neurons, and implicated in synaptic regulation (Lagerlöf et al., 2017). 

Boxer added that it remains unclear whether the trial’s adverse events and worse clinical outcomes were due to off-target effects. “These are pretty dirty drugs, and you can't interpret the tau PET without the context of everything else going on,” he said. “Such a large attenuation of atrophy may mean it’s affecting many things in the brain.”

Whether OGA inhibitors would affect other tauopathies differently is still an open question. The Spanish company Ferrer is conducting a Phase 1 trial of a different candidate for progressive supranuclear palsy. While the mechanisms of tau accumulation in PSP likely differ from those in Alzheimer's, Boxer said, the drug might cause similar off-target effects in both diseases.

Ceperognastat is one of three OGA inhibitors in trials for Alzheimer's and the first to have reached Phase 2. Biogen’s BIIB113 wrapped up its Phase 1 trial last year, but the company didn’t answer a question about its future plans for the molecule (Mar 2024 news). A spokesperson told Alzforum that the company is “working to analyze both internal and external insights of the study.”

Asceneuron is developing an OGA inhibitor called ASN51. It began Phase 2 last month, with a safety and biomarker trial that plans to enroll 78 people and run through 2026.—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

News Citations

  1. Finally, Therapeutic Antibodies Start to Reduce Tangles
  2. Can a Little Sugar Keep Tau From Souring Neurons?
  3. Therapeutic Contenders Target Hard-to-Reach Pockets of Tau

Therapeutics Citations

  1. Ceperognastat

Paper Citations

  1. Zachara NE, Akimoto Y, Boyce M, Hart GW. The O-GlcNAc Modification. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. Essentials of Glycobiology [Internet]. 4th edition.
  2. Lagerlöf O, Hart GW, Huganir RL. O-GlcNAc transferase regulates excitatory synapse maturity. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1684-1689. Epub 2017 Jan 31 PubMed.

External Citations

  1. Phase 1 trial
  2. Phase 1 trial
  3. Phase 2

Further Reading

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