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The chronic myeloid leukemia drug nilotinib (Tasigna) altered biomarkers in patients with moderately severe Parkinson's disease in a way suggesting potential for treating the condition, researchers for a single-center reported.

Nilotinib, a drug closely watched by the Parkinson's community because of its mechanism of action, appeared to be "reasonably safe" as adjunctive treatment at once-daily 150 mg and 300 mg doses and was detectable in cerebrospinal fluid (CSF), according to Charbel Moussa, MBBS, PhD, of Georgetown University in Washington, D.C., and co-authors.

Dopamine metabolites, α-synuclein oligomers, and tau were altered in CSF in response to the drug, compared with placebo, the team wrote in .

"Our research shows significant impact on safety and biomarkers," Moussa told MedPage Today. "This work will continue to phase III."

Just a few weeks ago, however, researchers in another phase II nilotinib study reached a completely different conclusion.

Top-line results from the multi-center trial prompted Tanya Simuni, MD, of Northwestern University in Chicago, and co-authors to that nilotinib "does not exert a clinically meaningful benefit or biological effect to benefit those with Parkinson's disease."

Data from NILO-PD have not been released yet, but among Parkinson's patients selected for the study -- and about did not qualify -- the drug had "very low [central nervous system] penetration, consistent with what has been observed in a carefully designed animal study," Simuni said.

"Nilotinib failed to alter dopamine turnover in the cerebrospinal fluid, one of the biomarkers that indicates neuroprotective effects," Simuni told MedPage Today. "Further, in clinical examinations, participants of the NILO-PD trial did not show an improvement in symptoms as measured by the Movement Disorders Society Unified Parkinson's Disease Rating Scale."

Based on these results, the NILO-PD steering committee decided "not to pursue further investigation of nilotinib for Parkinson's due to lack of plausible biological effect of the drug on the targeted mechanism of neuroprotection," she continued. "We presented our results to a panel of experts at the National Institute of Neurological Disorders and Stroke that came to the same conclusion."

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, and an of the drug in Parkinson's patients suggested possible benefit.

However, Simuni noted,"there are a number of other drugs in clinical development with better brain penetration that inhibit c-Abl." Nilotinib, which is approved for Philadelphia chromosome-positive chronic myeloid leukemia at 300 mg twice daily, carries a for QT prolongation and sudden death.

In their phase II study, Moussa and colleagues randomized 75 Parkinson's patients 1:1:1 to once daily oral doses of placebo, 150 mg, or 300 mg nilotinib for 12 months, on top of standard Parkinson's medications. Patients had moderately severe disease; 73% were men, and the mean age was about 68.

All patients received a single, random baseline dose of nilotinib as part of a pharmacokinetic and pharmacodynamic analysis. Because of this, researchers could not evaluate changes in exploratory biomarkers from baseline.

At 12 months, the dopamine metabolites homovanillic acid (P=0.04) and 3,4-dihydroxyphenylacetic acid (DOPAC; P=0.01) increased in the 150 mg group, compared with placebo. DOPAC also increased in the 300 mg group (P=0.01).

The 150 mg group, but not the 300 mg group, showed a reduction in CSF α-synuclein oligomers (P=0.03). Both groups had a significant reduction in hyperphosphorylated tau (P=0.01 for both).

The total number of adverse events was similar between groups (P=0.08). The number of serious adverse events (SAEs) rose significantly (P=0.03) as the dose of nilotinib increased: 16% for placebo, 24% for 150 mg, and 48% for 300 mg.

Patients in the 150 mg group were hospitalized for fall, hip fracture, prosthetic repair, aspiration pneumonia, orthostasis, and cellulitis. Patients in the 300 mg group were hospitalized for urinary tract infection, bronchitis, hip fracture, fall, and cellulitis. One participant had metastatic pancreatic cancer and developed a pulmonary embolism after biopsy and died. One participant was hospitalized for psychosis and suicidal ideation and attempted suicide.

No significant difference was seen in cardiovascular SAEs, which totaled four in the study.

"On the heels of recent negative phase III trials of the promising molecules isradipine and , the path ahead for nilotinib is therefore a narrow and difficult one," observed Alberto Espay, MD, MSc, of the University of Cincinnati and co-authors, in an .

"The conclusion that nilotinib is reasonably safe holds poorly to scrutiny," they wrote. "Overall, SAEs were significantly more common with nilotinib, 300 mg, compared with placebo and there was a nonsignificant but dose-dependent increased incidence in falls in the treated groups (placebo, 39%; nilotinib, 150 mg, 54%; nilotinib, 300 mg, 61%)." The study was underpowered to assess the occurrence of sudden cardiac death, the editorialists added.

While "the justification for a phase III trial is tenuous," it's possible the study may shed light on whether a certain type of Parkinson's patients might benefit from nilotinib, Espay and co-authors noted.

"Regardless of allocation, most patients in all three groups exhibited CSF oligomeric α-synuclein levels between 0.1 and 0.3 pg/mL at 12 months," they wrote. "Only two below-range outliers statistically separated the 150-mg nilotinib group from the others. Could it be that these two patients benefited from nilotinib and represent the appropriate target subtype?"

The trial has limitations, Moussa and co-authors noted. It was underpowered and performed in a single center. In addition, one in four screened participants were excluded from the study based on electrocardiographic findings, and cardiac disease may have limited this group of patients from being enrolled.

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