Parkinson’s therapy reduces disease biomarkers in 12-week trial
Alpha-synuclein, inflammation, nerve health markers lowered with risvodetinib
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- Risvodetinib is an oral experimental therapy being developed to treat Parkinson’s disease and address underlying cellular damage.
- A 12-week Phase 2 trial showed the oral therapy significantly reduced multiple disease-related biomarkers in patients.
- The markers reflected processes associated with nerve cell degeneration, mitochondrial health, and neuroinflammation.
Risvodetinib, an oral therapy Abli Therapeutics is developing for people with Parkinson’s disease, reduced multiple disease-related biomarkers, the company announced.
The findings come from an expanded analysis of the 201 Phase 2 study (NCT05424276), which enrolled patients with bradykinesia (slowed movement), a hallmark symptom of Parkinson’s.
The trial tested once-daily risvodetinib against a placebo for three months in people with early, untreated Parkinson’s. Earlier results suggested that risvodetinib stabilized disease status and severity, and improved patient quality of life.
The new biomarker analysis involved 7,300 individual measures from as many as 80 participants in the 201 study. It expanded on earlier skin-biopsy findings by adding longitudinal blood measures from 80 participants and cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord) measures from six participants, with samples collected at the start and end of the trial.
Eleven disease-related biomarkers measured in tissue, blood, and CSF responded to risvodetinib, according to a company press release, The analysis “has revealed surprising information, both about the underlying processes of disease and how patients respond to risvodetinib treatment,” said Milton Werner, Abli’s chairman and CEO.
‘How disease modification should look’
The markers that responded reflected processes associated with nerve cell degeneration, the health of mitochondria (the cell’s powerhouses), and neuroinflammation (inflammation in the nervous system).
“The outcomes indicate that the biological cascade of disease is reflected by these biomarkers and is substantially reversed in 12-weeks of once daily treatment with risvodetinib, including substantial reduction in phosphorylated alpha-synuclein, believed to be the causative agent of human PD [Parkinson’s disease],” said Werner. “In our view, this is how disease-modification should look.”
Risvodetinib, also known as ABLi-148009, is designed to block c-Abl kinases, a type of enzyme involved in cell signaling. These enzymes are thought to become overactive in Parkinson’s and may contribute to disease-related processes, including alpha-synuclein buildup, mitochondrial dysfunction, and inflammation.
Alpha-synuclein is a protein that can misfold and form toxic clumps in Parkinson’s. These clumps, which contain a modified (phosphorylated) form of alpha-synuclein, are considered a key feature of the disease and are thought to contribute to the damage and death of dopamine-producing nerve cells, which help control movement.
According to the company, all three tested doses of risvodetinib — 50 mg, 100 mg, and 200 mg, taken once daily — inhibited c-Abl kinase activity. The 100 and 200 mg doses substantially reduced alpha-synuclein biomarkers in the CSF, while all three doses reduced phosphorylated alpha-synuclein levels in blood.
All three doses suppressed markers of neuroinflammation, including the NLRP3 protein and pro-inflammatory molecules called cytokines, specifically interleukin-1 and interleukin-18.
The NLRP3 protein is a key component of the inflammasome, a molecular complex that, when activated, triggers a strong inflammatory response.
Abli said the findings suggest risvodetinib has a coordinated effect on disease mechanisms that affect the central nervous system (brain and spinal cord) and the peripheral nervous system, which includes nerves outside the brain and spinal cord.
Because the 201 study was not designed to prove that risvodetinib slows Parkinson’s progression, larger, longer studies will be needed to determine whether the biomarker changes translate into meaningful benefits for patients, researchers said.
The company is evaluating the potential of these biomarkers for diagnosis and prognostic applications, which will help inform its planned late-stage CAMPD trial. The trial’s main goal is to assess whether risvodetinib can slow or halt disease progression by measuring changes in the rate of clinical worsening. It will also examine whether changes in disease-related biomarkers track with patients’ clinical outcomes.
Abli said it will discuss the new findings with the U.S. Food and Drug Administration this month.
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