Nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates, according to recent data from a Phase 2 clinical trial.
These findings suggest that Novartis’ investigational therapy has the potential to promote long-term benefits in patients with Parkinson’s disease.
The study, “Nilotinib increases dopamine metabolism and reduces oligomeric: total alpha-synuclein ratio in Parkinson’s disease,” was recently presented during the 2018 World Congress on Parkinson’s Disease and Related Disorders (IAPRD), Lyon, France.
Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia. It blocks the activity of a protein called BCR-ABL that is known to support cancer development. But this protein also is intimately linked to several mechanisms in the brain, such as oxidative stress and alpha-synuclein-induced neurodegeneration, which play critical roles in Parkinson’s and other brain disorders.
Results of a small proof-of-concept Phase 1 trial (NCT02281474) performed at Georgetown University in Washington, D.C., revealed that treatment with two different doses of Nilotinib — 150 mg and 300 mg — could improve Parkinson’s patients’ motor skills and cognitive abilities. In addition, the treatment showed the potential to reduce levels of the protein alpha-synuclein, which is believed to contribute to destruction of brain nerve cells in Parkinson’s disease.
In the ongoing Phase 2 trial (NCT02954978) a total of 75 patients with mid-stage Parkinson’s disease with mild cognitive impairment were randomized to take one of four tested oral doses of Nilotinib -—150 mg, 200 mg, 300 mg, and 400 mg — or a placebo.
After a single treatment researchers evaluated several biomarkers of the disease, including the levels of alpha-synuclein and dopamine derivate compounds in patients’ cerebrospinal fluid (CSF).
The data revealed a significant increase in homovanillic acid (HVA) and DOPAC levels, suggestive of enhanced production and metabolism of dopamine just one to four hours after treatment.
Although researchers could not find significant changes in CSF total alpha-synuclein levels, low-dose Nilotinib therapy (150 mg and 200 mg) resulted in a reduction of the levels of abnormally clustered and toxic alpha-synuclein.
“The significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of Parkinson’s disease patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.
“These results suggest Nilotinib, in a dose dependent manner, may have a symptomatic effect through modulation of brain dopamine levels. Additionally, the significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of PD patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.
The team will continue the analysis of the collected data to further explore the impact of Nilotinib treatment on disease biomarkers’ levels both in the blood and CSF, after a single administration and 52-week daily treatment regimen.
A new Phase 2 trial, NILO-PD (NCT03205488), currently recruiting 135 participants, will further investigate the potential of Nilotinib in patients with moderate-to-advanced Parkinson’s symptoms.
The study will take place at 25 sites across the United States. It will compare the safety and effects on patients’ motor functions of once-daily Nilotinib versus placebo treatment, for up to 12 months.
https://parkinsonsnewstoday.com/2018/08/24/phase-2-trial-shows-nilotinib-potential-to-modulate-dopamine-in-parkinsons-patients/
No comments:
Post a Comment