Pauline Anderson

August 12, 2016

TORONTO — A new agent designed to regulate glucose metabolism in the brain significantly affects cognition in patients with mild to moderate Alzheimer's disease (AD), results of a small phase 2 trial suggest.

The study showed that over half of patients taking the drug (called T3D-959) experienced at least a 1-point improvement on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).

"This is a game changer," said John Didsbury, PhD, founder and CEO, T3D Therapeutics, the company developing the drug. "It's a whole new metabolic approach to treating Alzheimer's disease."

The ADS-cog changes seen with the new agent "are greater than with anything you'll see here at this whole scientific conference," said Dr Didsbury. He discussed his research with Medscape Medical News during the Alzheimer's Association International Conference (AAIC).

However, other experts are more cautious, saying it's too early to get excited about a trial that is small and open label.

Starved Brain

AD is caused by "starvation" of the brain that leads to inflammation and deposition of plaques and tangles, says Dr Didsbury, whose background includes diabetes research. The new oral agent is an insulin sensitizer, and so it improves glucose metabolism in the brain "dramatically," he said.

The drug helps turn on major signaling pathways that appear to be vital to memory, including the canonical wnt signaling pathway, insulin signaling, and insulin-like growth factor-1 signalling, he explained.

James Hendrix, PhD, director, global science initiatives, medical and scientific relations, Alzheimer's Association, says this target varies slightly from that of pioglitazone, a diabetes drug being tested in a phase 3 study dubbed the TOMORROW trial.

The ongoing multicenter, double-blind, randomized, placebo-controlled TOMORROW study is designed in part to evaluate the efficacy of low-dose pioglitazone as a treatment to delay onset of mild cognitive impairment in cognitively normal individuals at high genetic risk for AD.

T3D-959 and pioglitazone target similar pathways but "are slightly different in terms of selectivity and possibly different in the pharmacology that you get, so it's a similar approach" to trying to affect brain metabolism, but not exactly the same, said Dr Hendrix.

The current exploratory trial of T3D-959 included 36 patients, mean age 73 years, with mild or moderate AD (Mini-Mental State Examination score, 14 to 36) at three centers in the United States.

The patients took the drug in capsule form at 3 mg, 10 mg, 30 mg, or 90 mg once a day for 14 days.

According to a "loose" definition of responder (at least a 1-point improvement on ADAS-cog), 17 of 32 patients improved, by an average of 4.4 points at 2 weeks.

With a stricter definition of responder (a 2-point or better improvement), 14 patients improved, by about 4.78 points.

And with an even more strict definition of responder (a 3-point or greater improvement) almost a third of patients (10 of 32 patients, or 31%) responded, with an improvement of almost 6 points (5.74).

"This is a huge improvement," commented Dr Didsbury.

There was no difference in response between patients with mild or moderate disease.

The effects also seem to be durable; for all patients at all doses, the average ADAS-cog score improved by an additional 0.22 points after patients had been off the drug for 1 week, Dr Didsbury said.

The 10 patients who improved by 3 points or more at the end of drug treatment had an additional improvement of 0.29 points after being off the drug for 1 week, he said.

 An analysis with fluorodeoxyglucose–positron emission tomography neuroimaging also showed that the drug improved glucose metabolism in areas of the brain involved in AD, including the insula, cingulate, putamen, and fontal inferior cortex.

"Low sugar metabolism is a hallmark of this disease and is a better predictor of future cognitive decline than plaque load or tau load," according to Dr Didsbury.

None of the study participants experienced adverse effects, he said.

The drug can also affect metabolism outside the brain. "In particular, it can control lipid homeostasis and energy homeostasis by regulating fatty acid oxidation, energy dissipation, and mitochondrial respiration," said Dr Didsbury.

Dr Didsbury said he's not aware of any other company developing a similar agent.

Against the Grain

"We are the little mouse that roared," he said. "We are going against the grain, challenging the consensus science idea bubble that it's plaques or tangles causing AD. To us, these are manifestations of the disease, not a cause."

Because brain metabolic abnormalities are the "upstream driver" of AD, this helps explain why so many patients have amyloid plaques but don't get this disease, said Dr Didsbury.

In his view, these new results are more impressive than those shown for other drugs discussed at the meeting, including BACE 1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors, he said. Some posters at this year's AAIC meeting highlighted early results for agents that inhibit BACE 1, required to produce neurotoxic β-amyloid peptide, which is thought to play a crucial role in AD.

Dr Didsbury and his colleagues haven't looked at the effect of their new drug on levels of amyloid or tau. "The litmus test for us is how is it doing to the patient, and it's working."

Four of the original patients are now enrolled in a 26-week open-label extension study. After being off the drug for 2 to 4 months, they took the drug again for the extension study.

After completing another phase 2 trial, the company hopes to launch a phase 3 trial, said Dr Didsbury.

Longer and larger trials of this drug are needed, stressed Dr Hendrix. While the initial results "look promising" and "potentially exciting," Dr Hendrix said, "we have to temper that excitement with the knowledge that this is small and early, and it's an open-label trial so there is no placebo group for comparison."

The concept of AD being a sort of diabetes of the brain is being explored elsewhere. In addition to the TOMORROW trial, researchers are investigating an intranasal insulin in the hopes that it will enter the brain and affect metabolism and cognition; injected insulin does not cross the blood-brain barrier, he added.

"We will have to wait to know what is the best approach," said Dr Hendrix.

The study was funded by T3D Therapeutics. Dr Didsbury is founder and CEO of the company. Dr Hendrix has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2016. Abstract 390. Presented July 27, 2016.

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