How Novartis' cancer drug Tasigna restores critical dopamine that's lost to Parkinson's disease

Researchers at Georgetown University have been trying to repurpose Novartis’ cancer drug Tasigna to treat Parkinson’s disease since 2013, when they showed it could clear toxic alpha-synuclein protein clumps in the brains of mice. But it wasn’t until 2017, when they moved Tasigna into a small phase 2 trial, that they started to understand exactly how Tasigna—a tyrosine kinase inhibitor—might work in the brain to relieve Parkinson's symptoms.

The Georgetown researchers have gained new insights from that trial they believe offer critical clues to Tasigna’s action in the brain. They reported an increase in dopamine, the critical brain chemical that’s lost to Parkinson’s, among patients in the trial who were taking Tasigna (nilotinib). That increase, coupled with a decrease in neurotoxic proteins, may explain how Tasigna can stop the decline of both motor and non-motor functioning, they reported in the journal JAMA Neurology.

The trial included 75 Parkinson’s patients who either received 150 mg or 300 mg of Tasigna or a placebo. The trial was designed primarily to assess the safety of the drug in Parkinson’s, but the researchers also measured clinical outcomes, and they collected biomarkers from the patients’ cerebral spinal fluid.

They found that patients taking Tasigna had 20% less alpha-synuclein and 30% less tau, another toxic brain protein. They also had 50% more dopamine metabolites—a sign that clearing neurotoxic proteins may boost the ability of the brain to use dopamine.

After 15 months, motor ability improved among patients on the lower dose of Tasigna, while those taking placebo or the higher dose of the drug remained stable. All patients on Tasigna reported an improvement in quality of life.

The results suggested that Tasigna “stabilized the disease—a potential disease modifying effect that we haven't observed with any other agents," said lead investigator Fernando Pagan, M.D., Georgetown neurology professor and medical director of the GUMC Translational Neurotherapeutics Program, in a statement.

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Tasigna was approved by the FDA to treat chronic myeloid leukemia at a dose of up to 400 mg per day. The drug does carry a black box warning, however, because by inhibiting Abl tyrosine kinase—a protein that’s critical for cellular functioning—it can cause sudden death. So part of the mission of the Georgetown team was to determine whether the drug could be safely administered to Parkinson’s patients at lower doses and still be effective.

At both 150 mg and 300 mg, the drug did not inhibit Abl tyrosine kinase, the researchers reported. Only two patients withdrew from the phase 2 trial due to adverse effects.

That finding suggests that Abl inhibition is unlikely cause the lowering of neurotoxic proteins that the Georgetown team observed. It’s possible that the blocking of other tyrosine kinases may be causing the beneficial impact in the brains of Parkinsons’ patients, they suggested.

Novartis supplied Tasigna for the study but is not otherwise providing financial support to Georgetown, which owns the intellectual property rights for use of the drug in some neurodegenerative diseases. The Michael J. Fox Foundation was among the early supporters of the Tasigna research. The phase 2 was supported by the Lasky-Barajas Family Fund and other donors, Georgetown said.

In March, the Georgetown team published data from the phase 2 trial showing that Tasigna may have other benefits in the brain. At a dose of 200 mg, the drug seemed to boost levels of TREM2, an anti-inflammatory protein in the brain.

The phase 2 trial is expected to be completed in 2020. Then the clinical findings will need to be confirmed in larger studies involving diverse populations of patients, Pagan said.