Buntanetap lowered TDP-43 blood levels in people with Parkinson’s

The protein has been implicated in a number of neurodegenerative disorders

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by Andrea Lobo |

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Buntanetap significantly reduced the levels of TDP-43 protein in the blood of people with Parkinson’s disease who participated in a Phase 2a clinical trial, according to clinical data from its developer Annovis Bio.

The treatment also demonstrated a trend toward reducing other markers of inflammation.

“We are pleasantly surprised to see a statistically significant drop in TDP43 levels in just 10 patients and to see a strong trend in GFAP and NfL. To our knowledge this is the first time that a drug reduces the levels of TDP43 in humans, specifically here in [Parkinson’s disease] patients,” Maria Maccecchini, PhD, Annovis’s CEO, said in a press release.

At normal levels, TDP-43, or TAR DNA-binding protein 43, is crucial in various cellular processes, particularly in regulating RNA, the molecule that carries genetic information, and is involved in protein synthesis in cells.

When it’s highly active, however, it builds up into toxic clumps, just as alpha-synuclein does in Parkinson’s and beta-amyloid and tau do in Alzheimer’s disease. This aggregation impairs nerve cell function, induces inflammation, and contributes to neuronal death.

TDP-43’s abnormal accumulation has been implicated in several neurodegenerative diseases, namely Parkinson’s, Alzheimer’s, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS).

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Phase 3 trial of buntanetap expands to Europe

Measuring buntanetap in Parkinson’s patients’ blood

Buntanetap (previously known as ANVS401 or posiphen) is an oral small molecule that blocks translation, the process wherein the information in RNA is used to build a protein, and is designed to reduce the levels of harmful protein clumps in the brain.

In laboratory experiments in human neuronal cell SH-SY5Y, a standard cellular model for studying neurodegenerative disorders, buntanetap reduced TDP-43 levels, Annovis has demonstrated. It also reduced other proteins that accumulate to toxic levels in several neurological diseases, such as alpha-synuclein, beta-amyloid, and huntingtin in Huntington’s disease. This reduction is thought to reduce inflammation and nerve cell damage, preserving neurological function.

Recent developments in biomarker research let measures of these proteins be taken from blood instead of the cerebrospinal fluid that surrounds the brain and spinal cord, which required a more invasive procedure. This lets researchers follow variations in biomarker levels during the disease course and is not so burdensome to patients.

Here, researchers measured TDP-43 in the blood of 10 Parkinson’s patients treated with buntanetap in the company’s now completed Phase 2a trial (NCT04524351) and compared it with five patients who received a placebo.

A daily 80mg dose of buntanetap administered for 28 days significantly lowered TDP43 accumulation in blood plasma by 71.7% compared to the placebo group. Buntanetap also showed a tendency to reduce levels of the inflammatory factor GFAP (glial fibrillary acidic protein) and the axonal damage biomarker NfL (neurofilament-light chain).

“These biomarker data not only corroborate the mechanism of actions of buntanetap, but also provide a new way to stratify patients and understand their disease pathology,” Maccecchini said.

The Phase 2a trial included people with early Parkinson’s and Alzheimer’s, and found that buntanetap was safe at various doses when given once daily for 25 days. It also demonstrated the drug improved cognitive and motor skills in people with Parkinson’s.

The results supported starting a Phase 3 clinical trial (NCT05357989) in August 2022 wherein people with early-stage Parkinson’s patients, aged 40 to 85, received buntanetap or a placebo, on top of their standard of care medications for up to six months.

Besides assessing the treatment’s safety and tolerability, the trial will also evaluate changes in the patients’ ability to perform everyday tasks and motor function, cognitive function, and blood biomarkers.

“We will measure the above biomarkers in the plasma of the patients that are presently in our phase 3 [Parkinson’s disease] study to show the effect our drug has on the course of the disease over a six-month period,” Maccecchini said.