Lessons Learned From The Nilotinib/Parkinson's Study
Is Nilotinib safe and effective for Parkinson’s disease patients?
This very question has stirred controversy since Moussa and colleagues published encouraging results5 about Nilotinib as a treatment for Parkinson's.
The study enrolled 12 participants with Parkinson's or Dementia with Lewy Bodies. The patients were randomized to either 150 or 300 mg Nilotinib. The authors sought to answer these questions:
- is Nilotinib a safe and tolerable drug for Parkinson's patients?
- what's the pharmacokinetic profile of low-dose Nilotinib?
The authors also investigated the efficacy of Nilotinib indirectly, but described these endpoints as "exploratory" in contrast to the primary endpoint of safety and tolerability.
Since Moussa's 2015 paper, a lot of hype has been generated about Nilotinib for Parkinson's disease. There's a big incentive for media outlets to make hyperbolic claims based on tentative medical news. Patients also understandably like reading uplifting news, since Parkinson's is so devastating and currently available treatments do not alter the disease course.
Researchers have responded in an effort to temper enthusiasm over Nilotinib with sober words of warning:
- Nilotinib - Differentiating the Hope from the Hype.10
- Media hype: Patient and scientific perspectives on misleading medical news.11
There's simply not enough data to conclude one way or another whether Nilotinib is effective for Parkinson's. As Moussa's group acknowledges, their study was limited. They lacked a control group and the study was under-powered with only 12 participants. This means that there's no way to exclude a placebo effect.
Critics of the study contend that the efficacy endpoints used are misleading.
Moreover, Nilotinib is also not a benign drug. It is an anti-cancer drug with serious side effects.
In Wyse et al 10 sum up the critic's position nicely:
Many neurology experts felt that the global media exposure which followed the initial announcement of the results was an object lesson on how not to report a small clinical trial that has no placebo control. While patients suffering from Parkinson’s disease (PD) and related alpha-synucleinopathies continue to feel an urgent need for better therapies, this news story inappropriately fed their hope with hype.
Those considering Nilotinib to treat Parkinson’s disease should be cautiously optimistic. More research is needed before its therapeutic effects can be conclusively stated.
Strikingly, despite the lack of evidence for efficacy, Wyse reported that there's been an uptick in off-label prescriptions of Nilotinib for Parkinson's. This is a cautionary tale for all of us about what can happen when tentative study results are reported hyperbolically.
What is Nilotinib?
Nilotinib (Tasigna) is a tyrosine kinase inhibitor used to treat certain forms of chronic myeloid leukemia6.
How Does Niltonib Work?
Tyrosine kinases are enzymes that play a role in several cellular processes.
In leukemia, a tyrosine kinase called ABL fuses with another protein called BCR to form BCR-ABL. This fusion causes BCR-ABL to activate several pro-survival processes, leading to cancer.
Nilotinib binds tightly to BCR-ABL to hinder its function. Blocking BCR-ABL function causes the cells to undergo autophagy. Autophagy is a process in which improperly functioning components of the cell and sometimes the whole cell itself is destroyed67.
Why Nilotinib For Parkinson's Disease?
Parkinson’s disease is complex and poorly understood.
By the time patients with Parkinson's become symptomatic, dopamine-producing neurons in specific brain regions are destroyed are lost. Dopaminergic neurons are highly metabolically active and sensitive to oxidative stress. It's the death of these neurons that leads to motor and cognitive problems.
Another aspect of Parkinson’s disease stems from the accumulation of protein aggregates. A protein called α-synuclein accumulates in the brain to form Lewy bodies.
Nilotinib may partially ameliorate this neurodegenerative process in the following ways:
- Low-dose Nilotinib (1-10mg per day) degrades abnormal α-synuclein1
- Nilotinib improves dopamine levels and motor and reasoning functions in animal models of Parkinson’s disease and Alzheimer’s disease41
- Nilotinib protects dopamine-producing nerve cells21
Another way Nilotinib may treat parkinson’s disease is by blocking c-Abl activity. Activated c-Abl also inhibits a protein called parkin. Parkin is responsible for keeping levels of another harmful protein, PARIS, down. When c-Abl inhibits Parkin, PARIS levels increase, accumulate and cause death of neurons that release dopamine.
A 2014 study of animals with Parkinson’s disease like symptoms found that treatment with Nilotinib blocked the activity of c-Abl and reduced the level of PARIS in the brain. This prevented nerve cell loss and behavioral defects2
How Does Nilotinib Affect Parkinson’s Patients?
Interest in Nilotinib as a treatment for Parkinson’s disease has recently spiked solely based findings from Moussa's 2015 study.
Moussa and colleagues conducted a clinical study in which 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies were treated with 150mg or 300mg of Nilotinib/day for 6 months. The authors drew the following conclusions:
- Nilotinib reduced Parkinson’s disease-related oxidative stress (i.e. reduced cell damage)
- Nilotinib penetrates the blood brain barrier (if the drug doesn't get into the brain, it's useless for Parkinson's!)
- Nilotinib may slow the depletion of dopamine in the brain
- Reduced concentrations of α-synuclein in the cerebral spinal fluid of patients with Parkinson’s disease
- Motor symptoms improved following treatment
- Low-dose Nilotinib is relatively safe and well-tolerated
To treat patients with chronic myeloid leukemia, Nilotinib is taken orally twice a day without food at a dose of 600-800mg a day. Doctors also advise that it be taken on an empty stomach (1hr before eating or 2h after eating)9.
Patients prescribed Nilotinib should also avoid grapefruit. That's because grapefruit inhibits CYP 3A4 enzyme which metabolize various drugs, including Nilotinib.
The subjects in the Moussa study took 150 or 300mg daily5. Even though the dosage used in the Moussa study was much lower than that typically used to treat leukemia, the study suggests that it is relatively safe and yet still effective.
Nilotinib Side Effects
Patients and physicians should remain cautious about Nilotinib because there's insufficient evidence for benefit and because Nilotinib adverse effects are serious.
Chronic Myeloid Leukemia
Patients with chronic myeloid leukemia that take Nilotinib experience several side effects including3:
- skin rash
- joint or muscle aches or pain
- back pain
- temporary hair loss
- cold symptoms (stuffy nose, sneezing, cough, or sore throat)
Patients in the Pagan study with either Parkinson’s disease dementia or dementia with Lewy bodies experienced some of the following symptoms. With such a small sample size and no placebo arm, it remains unclear if these adverse effects were related to Nilotinib:
- Mild blurry vision
- Weight loss
- Back pain
- Confusion and dizziness
- Mild hallucinations
- Mild paranoia
- Renal and urinary disorders
- Skin irritation
Some patients in the study also experienced major adverse events that may or may not be related to treatment including:
- Heart attack
- Urinary tract infection
Should You Take Nilotinib For Parkinson’s Disease?
Too little data is available to provide a verdict on Nilotinib for Parkinson's. Only one major study has been conducted and it was underpowered (i.e., a small number of participants were enrolled). The Pagan study had major limitations and confounds including:
- Lack of a control group (without this group, it is unclear if the Nilotinib effect is a placebo effect )
- Small sample size (it is difficult to draw conclusions on effects and side effects with only 12 people)
Interestingly, some critics suggests that the increase in dopamine in the cerebral spinal fluid in the Pagan study may actually be a withdrawal symptom from ending treatment with a monoamine oxidase-B (MAO-B) inhibitor.
Dopamine levels were estimated by measuring the byproduct of its breakdown (homovanillic acid) in patients' cerebral spinal fluid.
But increases in the byproduct can also be produced when the MAO-B is no longer taken8. According to Wyse and colleagues10, this approach is also problematic because homovanillic acid levels vary greatly between patients and are poorly correlated with disease progression.
More studies are needed to establish the safety and efficacy of Nilotinib in Parkinson's disease patients.
Hebron, M., Lonskaya, I., & Moussa, C. (2013). Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models. Hum Mol Genet, 3315-28. ↩
Karuppagounder, S., Brahmachari, S., Lee, Y., Dawson, V., Dawson, T., & Ko, H. (2014). The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci Rep, 4874. ↩
Lang, A., Mounier, M., Roques, M., Chretien, M., & Boulin, M. (2015). A retrospective study of the prescribing and outcomes of tyrosine kinase inhibitors in chronic myeloid leukaemia over a period of more than 10 years. Journal of clinical Pharmacy and Therapeutics. ↩
Lonskaya, I., Hebron, M., Desforges, N., Franjie, A., & Moussa, C. (2013). Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med, 1247–1262. ↩
Pagan, F., Hebron, M., Valadez, E., Torres-Yaghi, Y., Huang, X., Mills, R., et al. (2016). Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies. J Parkinsons Dis, 503-17. ↩
Pasic, I., & Lipton, J. (2017). Current approach to the treatment of chronic myeloid leukaemia. Leukemia Research, 65-78. ↩
Salomoni, P., & Calabretta, B. (2009). Targeted therapies and autophagy: new insights from chronic myeloid leukemia. Autophagy, 1050-1. ↩
Schwarzschild, M. (2017). Could MAO-B Inhibitor Withdrawal Rather than Nilotinib Benefit Explain the Dopamine Metabolite Increase in Parkinsonian Study Subjects? J Parkinsons Dis, 79-80. ↩
Skorski, T. (2011). BCR-ABL1 kinase: hunting an elusive target with new weapons. Chem Biol, 352-3. ↩
Wyse RK, Brundin P et al.. Nilotinib - Differentiating the Hope from the Hype. J Parkinsons Dis. 2016 Jul 12;6(3):519-22 ↩
Robledo I, Jankovic J. Media hype: Patient and scientific perspectives on misleading medical news. Mov Disord. 2017 Apr 3;(): ↩