CTAD: T3D’s Experimental Alzheimer’s

CTAD: T3D’s Experimental Alzheimer’s Pill Is Insulin for the Brain

By | October 25th, 2023

T3D Therapeutics is betting that Alzheimer’s disease is caused by an underlying problem with the brain’s metabolism, causing it to starve. Their drug T3D-959 attempts to treat Alzheimer’s by helping the brain feed itself again.

At the 16th Annual Clinical Trials in Alzheimer’s Disease (CTAD) this week, T3D Therapeutics shared early data on an experimental Alzheimer’s pill they’re calling T3D-959. Rather than targeting the beta-amyloid plaques and tau tangles characteristic of Alzheimer’s disease, T3D-959 is designed to stop what T3D’s scientists believe is the underlying cause of neurodegeneration: a failure in energy metabolism in the brain — or, in other words, the brain starving itself to death. T3D-959, they say, is designed to halt Alzheimer’s by spurring a starving brain feed itself again.

The Phase 2 data presented at CTAD shows some early evidence that the T3D-959 pill could slow cognitive decline. The trial so far was done in a study of 250 patients with mild-to-moderate Alzheimer’s disease. Trial administrators tested the drug’s effects on cognitive decline over the course of 24 weeks, compared to placebo. While the overall trial was not positive, the researchers found one subgroup, defined after the trial, did appear to benefit.

The study results have not yet gone through the peer-review process (in which other scientists scrutinize the data before publishing it in a scientific journal).

“We have found clinical evidence of a modification of multiple Alzheimer’s disease pathologies associated with amyloid plaques,” T3D Therapeutics CEO John Didsbury told Being Patient. “We see an improvement in cognition and a high safety advantage over marketed therapies.” 

Again, the results were mixed across the trial, and it’s unclear whether the drug — and its innovative approach — works, but based on the positive results from one sub-group, the company will conduct a larger clinical trial of the drug, which is expected to begin within the next two years.  

How does Alzheimer’s drug candidate T3D-959 work?

According to Didsbury, T3D’s experimental Alzheimer’s pill comes in when Alzheimer’s causes changes in metabolism in the brain. These changes happen early on, before other disease processes begin.

“We’re treating Alzheimer’s disease as a metabolic disorder,” Didsbury explained. In this disorder, the cells start to starve because they can’t efficiently process and use glucose, fats, and cholesterol for energy or to maintain proper brain function.

When the cells aren’t able to use energy efficiently, it causes damage to the cells and leads to a build-up of beta-amyloid plaques and tau tangles.

Even worse, Didsbury explained, the brain becomes less responsive to insulin, a signal that tells cells to start using glucose for energy. Problems with insulin resistance and metabolism elsewhere in the body can also cause diabetes, a major risk factor for developing Alzheimer’s disease. (The T3D in T3D Therapeutics’ name refers to the idea that Alzheimer’s is a form of diabetes that affects the brain.)

T3D-959 activates two master metabolic switches in the brain called PPARδ/γ, which can fix these metabolic problems.

“We’re really feeding the brain by making the cells responsive to insulin so that they can process glucose for energy,” Didsbury said, adding that the drug could potentially work across different stages of the disease.

T3D Therapeutics isn’t the only company trying to address metabolic dysfunction to treat Alzheimer’s disease — Novo Nordisk is currently testing their blockbuster anti-diabetes and weight loss drug semaglutide (marketed as Wegovy for weight loss), which could also treat or prevent the disease.

Finding the correct dose and the right patient with blood biomarkers

In this new T3D pill’s Phase 2 trial, the 250 trial participants were randomly split into to four different groups to test different doses of the drug — 15 mg, 30 mg, and 45 mg daily — as compared to a placebo. (Participants didn’t know what dose they were receiving, or whether they were in fact receiving the drug or the placebo.)

Researchers found that the participants with high levels of an Alzheimer’s blood biomarker called the plasma pTau-217/Non-pTau-217 were most likely to experience slower cognitive decline while taking the drug. 

They also found that the 30-mg dose was most effective in reducing the levels of other Alzheimer’s biomarkers and slowing down a person’s rate of cognitive decline overall.

In their next trial, Didsbury said they will use blood biomarkers to zero in on patients most likely to respond to the treatment. He also noted that approximately 55 percent of Alzheimer’s patients may have these biomarkers. In other words, if the T3D pill proves safe and effective in the coming years, it could be applicable as an approach to slowing cognitive decline for a bit more than half of people living with Alzheimer’s.

UPDATED 27 October, 2023, 10:28 a.m. ET – Context was added around the trial findings — they weren’t all-out positive. Just one sub-group of participants showed positive results, and more research is needed.

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