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The chronic myeloid leukemia drug nilotinib (Tasigna) did not produce biological or clinically meaningful effects that would benefit people with Parkinson's disease, the trial suggested.

Over 6 months, nilotinib had no effect on symptoms or disease progression in people with moderate to advanced Parkinson's in the phase IIa study, though it appeared safe and tolerable at both 150 mg and 300 mg doses in a population with very stringent inclusion criteria, reported Tanya Simuni, MD, of Northwestern University in Chicago.

"Neither dose of the drug also showed any signal of symptomatic efficacy in either motor disability or other exploratory outcomes," Simuni said in an interview with 名媛直播. The study was not powered to assess efficacy, she noted, but nilotinib had low cerebrospinal fluid (CSF) exposure and failed to change dopamine or its metabolites.

The findings were presented in an of late-breaking research that was part of the , a platform for research from the AAN annual meeting, which was cancelled due to the COVID-19 pandemic.

Nilotinib inhibits (c-Abl), a protein linked to cellular pathways associated with Parkinson's. Cell and animal studies have shown that nilotinib may reduce α-synuclein pathology. In 2016, a study of the drug in Parkinson's patients by Georgetown University researchers suggested possible benefit.

Georgetown researchers also studied nilotinib for 1 year in a single-center phase II trial of 75 Parkinson's patients and reported it was "reasonably safe" as adjunctive treatment at once-daily 150 mg and 300 mg doses. Compared with placebo, dopamine metabolites, α-synuclein oligomers, and tau were altered in the CSF in response to the drug, they said. In that trial, the number of serious adverse events rose significantly as the nilotinib dose increased: 24% for 150 mg, and 48% for 300 mg.

The two phase II studies suggest that "motor scores trended in the direction opposite to that hypothesized and safety was decidedly problematic," observed Alberto Espay, MD, MSc, of the University of Cincinnati, who wasn't involved with either nilotinib trial.

Nilotinib is approved for Philadelphia chromosome-positive chronic myeloid leukemia at 300 mg twice daily and carries a for QT prolongation and sudden death. Because of that, NILO-PD had strict inclusion/exclusion criteria and screened out 40% of potentially eligible participants, Simuni said.

studied 75 moderate to advanced Parkinson's disease patients randomized 1:1:1 to 150 mg or 300 mg nilotinib once daily or placebo for 6 months, in addition to standard Parkinson's medication. The study ran in 25 sites from November 2017 to August 2019.

Besides evaluating safety and tolerability, the study aimed to assess the symptomatic effect of nilotinib, measured by change in MDS-UPDRS part III over time. The study also looked at nilotinib's effect on Parkinson's disability progression, measured by change in the Part III in "off" state between baseline and 6 months.

Most NILO-PD participants were male and white. At baseline, the mean age in each of the treatment groups ranged from 61 to 67, and mean levodopa equivalent daily doses ranged from 972 mg to 1,066 mg.

Most patients found the drug tolerable. One treatment-related serious adverse event occurred in the nilotinib 300 group; none occurred at the lower dose.

MDS-UPDRS Part III "on" and "off" scores showed no significant changes over time. Quality-of-life measures also did not change.

At 3 months, nilotinib CSF levels were substantially below the level needed for c-Abl inhibition, the researchers observed. CSF dopamine or its metabolites -- 3-4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) -- remained unchanged at 3 months.

"Nilotinib is not the best molecule to assess the therapeutic potential of c-Abl inhibition for Parkinson's disease," Simuni stated. "This is important to communicate because nilotinib is commercially available. The 2016 paper sparked substantial interest in the Parkinson's community and patients have been seeking the drug."

However, the findings do not refute the hypothesis that c-Abl inhibitors have potential neuroprotective effect, Simuni emphasized. "The pathway is promising," she said. "There are other molecules in development that may have different outcomes."

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