12 Aug 2020

This year’s virtual Alzheimer’s Association International Conference featured no new efficacy data from large clinical trials, but there were some snippets of news from early phase studies. CT1812 by Cognition Therapeutics (CogRx) seemed to knock Aβ off its putative receptors in people with Alzheimer’s disease and reverse changes to the AD CSF proteome, while Alector’s passive immunotherapy against sortilin boosted progranulin levels in frontotemporal dementia patients. Boehringer Ingelheim outlined Phase 2 data that led it to discontinue its glycine transporter inhibitor for AD last February.

In preparation for an upcoming efficacy trial, researchers from CogRx chose proteomics to tease out effects of their drug candidate CT1812. Research indicates this antagonist of the sigma2 receptor displaces Aβ oligomers from prion receptors on the cell surface, reducing Aβ toxicity.

At AAIC, Susan Catalano from the Pittsburgh-based company presented data from the first study of 19 people with mild to moderate AD, who were treated for 28 days, as well as from the first 24 patients who completed a subsequent six-month Phase 2 trial. The latter, called SHINE, assesses safety, cognition, and biomarker measures of synaptic damage in 62 people with mild to moderate AD. Each received daily placebo, 100 mg, or 300 mg CT1812. Cognition as a primary endpoint was assessed with the ADAS-Cog 11 at baseline, then again at days 40, 100, and 185 of treatment. Three other trials of this drug are in progress.

For SHINE, Catalano reported a trend toward improvement on the ADAS-Cog11 in the drug group compared with placebo at the end of the six months of treatment. Other cognitive measures, including the MMSE, ADASCog13, and other dementia indicators such as attention and executive function all showed a trend toward improvement, she said.

Biomarker data from the 28-day trial of 19 people suggested the drug might be engaging its target as proposed. As measured by native western blots, Aβ oligomers in the CSF dropped by half from baseline in people on placebo, while they increased slightly in patients taking 90, 280, or 560 mg of CT1812 daily. Catalano showed only the percentage change for Aβ oligomers and only pooled data from the treatment groups because the number of patients in each was so low, she said. CSF levels of Aβ monomers stayed unchanged, as did SNAP-25 and neurofilament light. However, neurogranin and synaptotagmin-1 levels, as measured by ELISA, fell slightly, which might indicate fewer synapses are degenerating (Dec 2017 news). 

To get an idea of what might be going on in neurons, the scientists used CSF proteomics to ask what changed in response to the drug. First, they looked at about 500 CSF proteins that previously had been implicated in synaptic biology (Lleó et al., 2019). Twenty-five of these, including proteins involved in synaptic structure and function, either rose or fell in the drug groups compared with placebo, suggesting something was happening to synapses.

Next, the researchers looked to see if CT1812 reversed changes seen in AD CSF relative to healthy controls (Higginbotham et al., 2019). In other words, if more of a given protein was found in AD CSF than in control CSF, would CT1812 squelch that difference or even reverse it? Again, about 20 proteins were shifted by CT1812, such that if they had been elevated in AD, they were suppressed in the drug arm, and if they had been suppressed in AD, they increased in the drug arm.

Lastly, Catalano reported that CT1812 decreased phosphorylation of tau at dozens of sites and increased it at six. Most of these sites are phosphorylated by enzymes other than GSK3β, though some GSK3β sites, including T205, S262, and T217, were less phosphorylated in the drug group. T181 seemed unaffected. Recent evidence suggests that T217 and T181 are phosphorylated very early in the disease trajectory in response to Aβ toxicity (Jul 2020 conference news). 

What does this mean? It remains to be seen. Catalano said that the drug reverses 6 to 7 percent of the protein changes seen in AD. “We don’t yet know what it means to move 6 percent of those proteins after a month on drug,” she said. She noted it will be important to track these changes in future trials and also figure out if any of these markers correlate with cognitive scores. “In previous trials [of other drugs], we have seen changes in every single biomarker but no effect on cognition,” she said. CogRx is planning an efficacy study in 540 volunteers, sponsored by the NIA and to be run by the Alzheimer’s Clinical Trial Consortium.

A Boost for Progranulin
AL001 is an anti-sortilin antibody currently in Phase 1 trials for treating frontotemporal dementia in people who have progranulin haploinsufficiency. It, too, is showing promise based on biomarker readouts presented at AAIC.

The rationale with AL001 is that blocking sortilin-mediated endocytosis will extend the half-life of progranulin, improve lysosomal function, and slow or reverse clinical decline. In his presentation, Robert Paul, Alector, South San Francisco, reported results indicating that 12 days after a single dose of the antibody, progranulin in CSF had risen in six asymptomatic GRN mutation carriers. In eight symptomatic carriers, one dose of AL001 every two weeks for six weeks doubled CSF progranulin.

The treatment also reduced CSF levels of osteopontin and chitotriosidase, markers of inflammation and gliosis, respectively, and increased cathepsin B, an indicator of lysosomal function. CSF NfL, a marker of axonal damage, also trended down. Interim analysis of 10 symptomatic GRN mutation carriers enrolled in a Phase 2 trial suggested the antibody was well tolerated, Paul said. It restored plasma progranulin to normal levels beginning about 10 days after treatment began.

Lastly, in the didn’t-pass-muster category, Glen Wunderlich from Boehringer Ingelheim, Burlington, Ontario, reported that the glycine transporter BI 425809 inhibitor did not improve cognition in a 12-week Phase 2 trial. The company had announced this past February that it would stop development of this drug for AD, though a trial is still ongoing for schizophrenia.—Tom Fagan

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References

Therapeutics Citations

1. CT1812
2. Latozinemab
3. Iclepertin

News Citations

1. Elusive or Not, Aβ Oligomers Are in BioPharma Crosshairs 13 Dec 2017
2. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics 29 Jul 2020

Paper Citations

1. Lleó A, Núñez-Llaves R, Alcolea D, Chiva C, Balateu-Paños D, Colom-Cadena M, Gomez-Giro G, Muñoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Lladó A, Molinuevo JL, Tainta M, Clarimón J, Spires-Jones T, Blesa R, Fortea J, Martínez-Lage P, Sánchez-Valle R, Sabidó E, Bayés À, Belbin O. Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid. Mol Cell Proteomics. 2019 Mar;18(3):546-560. Epub 2019 Jan 3 PubMed.

External Citations

1. Higginbotham et al., 2019

Further Reading

No Available Further Reading