Oral NT-0796 for Parkinson’s shows promise in early clinical trials

NodThera now testing therapy in patients in Phase 1/2 biomarker study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Following promising new data from healthy volunteers in early clinical trials, NodThera now is testing its oral treatment candidate NT-0796 in a Phase 1b/2a biomarker study involving people with Parkinson’s disease.

The biotech company announced the positive results from its first-in-human Phase 1 study (ACTRN12621001082897), which found that the experimental therapy had good pharmacological properties, readily entered into the brain, and was well-tolerated in healthy people.

NT-0796 also demonstrated anti-inflammatory activity, consistent with its expected inhibitory effects on the NLRP3 inflammasome — a pro-inflammatory signaling complex implicated in Parkinson’s and a range of other diseases.

Another experimental NLRP3 inhibitor from NodThera, called NT-0249, also was shown to inhibit NLRP3 and be well-tolerated in another Phase 1 study (ACTRN12622000195752).

“As the burden of non-communicable diseases continues to rise globally, targeting chronic low-grade inflammation, through selective modulation of the NLRP3 inflammasome, holds enormous potential for the treatment of these diseases,” Alan Watt, CEO of NodThera, said in a company press release, adding, “These excellent clinical data from both clinical candidates reinforce our confidence that NodThera has the clinical tools to address these challenges.”

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NodThera to test NLRP3 inhibitors in Parkinson’s clinical trials

The NLRP3 inflammasome is a multi-protein signaling complex that normally works to detect cellular threats. Upon its activation, in response to cell stress or damage, certain pro-inflammatory signaling molecules are released.

An increasing body of evidence suggests that this pathway contributes to the chronic inflammation that’s a key driver of neurodegeneration — the progressive loss of function and ultimate death of nerve cells — in Parkinson’s. It’s also implicated in a range of other inflammatory diseases, including those affecting the brain and the rest of the body (periphery).

NodThera is working to develop NLRP3 inflammasome inhibitors that may be useful for a variety of these diseases.

[The] oral, small molecule, clinical candidates NT-0249 and NT-0796 [demonstrated] … potentially best-in-class clinical profiles with significant anti-inflammatory effects.

In particular, the company aims to develop molecules with an ability to cross the selective blood-brain barrier, a tight-knit cellular membrane that works to keep molecules circulating in the bloodstream out of the brain. While this barrier, known as the BBB, protects the brain from potential harm, it also can prevent medications and therapies from exerting their effects in brain tissue. Crossing the BBB is a major hurdle when developing treatments for neurological diseases.

Both NT-0796 and NT-0249 are NLRP3 inhibitors. One difference between them lies in the part of the brain on which each exert its effects, according to NodThera.

In Phase 1 studies involving healthy adults, both NT-0796 and NT-0249 were found to reach the cerebrospinal fluid (CSF) — the fluid surrounding the brain and spinal cord. That indicated that the therapies are brain-penetrant, or able to cross the BBB.

Both experimental molecules reduced key biomarkers of NLRP3-associated inflammation, in addition to being safe and well-tolerated.

The “oral, small molecule, clinical candidates NT-0249 and NT-0796 [demonstrated] … potentially best-in-class clinical profiles with significant anti-inflammatory effects,” the company stated.

Now, NT-0796 is being evaluated in a Phase 1b/2a biomarker study designed to investigate its effect on inflammatory and Parkinson’s disease-specific biomarkers in the blood and CSF.

The panel of biomarkers to be evaluated was chosen based on preclinical data, and will include pro-inflammatory molecules as well as activation markers for microglia and astrocytes — two types of brain-resident support cells thought to drive inflammation in Parkinson’s.

All markers will be relevant to the expected downstream effects of NLRP3 inhibition.

The study’s first phase, involving healthy elderly adults, is underway. It’s employing a modified formulation of NT-076 that is also expected to be used in the trial’s second phase. That second part will include Parkinson’s patients.

“Our strategy to design highly differentiated and brain penetrant molecules, which combines a deep understanding of NLRP3 inhibition, pharmaceutical neuroscience expertise and precision molecular design, is delivering on the promise that NLRP3 inflammasome modulation can change the treatment paradigm for chronic peripheral and neurodegenerative diseases,”  Watt said.