reversal of Parkinson’s symptoms?

[Farooqji]

Alan Hoffman says nilotinib has changed his life. Just weeks after he started taking the drug in a clinical trial, he began to feel himself recovering from his Parkinson’s disease.

newscientist.com/article/dn...

[jimcaster]

One concern I have about this is that the story is more than 3 years old. Hopefully, more recent studies regarding Nilotinib will be published soon.

[Rhyothemis in reply to jimcaster]

There's an ongoing Phase 2 trial; projected study completion date is July 2020:

clinicaltrials.gov/ct2/show...

There's another one, due to be completed in October 2020:

clinicaltrials.gov/ct2/show...

[ElliotGreen in reply to jimcaster]

See what I found, below.

[Farooqji]

I think one of our forum members is also taking nilotinib. Will have to be searched

[jimcaster in reply to Farooqji]

Yes. I believe FMundo is.

[ElliotGreen]

Here's a recent (Aug 2018) news article which includes mention of the results of a Phase 2 trial and the current Phase 2A trial.

parkinsonsnewstoday.com/201...

It references this following proceedings from a recent academic conference. If you open that pdf and search for nilotinib, you will find that there are TWO abstracts about drug trials for the drug. The first describes the results of a Phase 2 Trial, and the second abstract is about the current Phase 2A trial.

(WARNING, LARGE PDF 202 PAGES)

iaprd-world-congress.com/in...

Here is the first abstract in full. (The results of a Phase 2 Trial.) It looks intriguing:

TITLE: Nilotinib increases dopamine metabolism and reduces oligomeric:total alpha-synuclein ratio in Parkinson’s disease.

Background: Our pre-clinical and open label phase I data indicate that the tyrosine kinase inhibitor (TKI) Nilotinib may improve motor symptoms and cognition, reverse dopamine loss and reduce brain alphasynuclein.

Methods: This is a phase II, open label, random single dose (RSD) study in mid-stage PD patients with mild cognitive impairment (MCI) to evaluate the effects of Nilotinib on disease biomarkers of PD. Cerebrospinal fluid (CSF) from 75 patients was examined to assess changes in the levels of CSF alpha-synuclein and the dopamine metabolite homovanillic acid (HVA) and 3,4-Dihydroxyphenylacetic acid DOPAC as primary disease biomarkers. A total of 15 patients in each of 5 randomized study groups, including placebo, 150mg, 200mg, 300mg and 400mg Nilotinib had lumbar punctures at 1-4 hours after a single time oral drug administration.

Results: CSF biomarkers analyses showed a statistically significant increase in the level of CSF HVA and DOPAC. No change was detected in total levels of CSF total alpha-synuclien, but lower dose (150mg and 200mg) resulted in a significant decrease of oligomeric;total CSF alpha-synuclein. Further analysis will be performed to compare plasma and CSF levels of these biomarkers between this single time administration and 52-week treatment.

Conclusions: These data suggest that a single time oral administration of Nilotinib may increase brain dopamine levels and metabolism. 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 longterm disease modifying effect. Importantly, the dose response of oligomeric alpha-synuclein and HVA changes to nilotinib suggests that the dose administered may depend on the stage of disease to potentially halt PD progression.

[ElliotGreen]

The increase in DOPAC looks promising. DOPAC is non-toxic. The alternative is toxic oxidized dopamine.

This 2017 article in Science magazine is important. It found that when the biological machinery for dealing with oxidative stress is impaired, you get LESS DOPAC and MORE harmful oxidized dopamine.

TITLE: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

science.sciencemag.org/cont...

"Dopamine can either be converted into nontoxic downstream metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), or form toxic dopamine quinones and aminochrome..."

"[This paper] identified a toxic cascade of mitochondrial and lysosomal dysfunction in human neurons derived from patients with Parkinson's. The dysfunction was mediated by accumulation of oxidized dopamine and α-synuclein..."

[PixelPaul]

By chance, has anyone here participated in these trials?

[jimcaster in reply to PixelPaul]

Yes. I believe FMundo is.

[ElliotGreen]

Already approved in USA for leukemia as drug TASIGNA. Can cause this serious side effect:

"TASIGNA can cause QTc prolongation, a possibly life-threatening heart problem. QTc prolongation causes an irregular heartbeat, which may lead to sudden death. Call your doctor right away if you feel lightheaded, faint, or have an irregular heartbeat while taking TASIGNA."

source: us.tasigna.com/#

[ElliotGreen in reply to ElliotGreen]

There is a class action lawsuit regarding this drug. Again, there is a connection between nilotinib (tasigna) and cardiovascular problems.

tasignalawsuit.com/

tasignalawsuit.com/tasigna-...

"The first major peer-reviewed study which specifically examined Tasigna atherosclerosis was published in the American Journal of Hematology. Using post-market clinical data, the study concluded that 25% of Tasigna patients experienced a "vascular event" and 16% suffered from peripheral arterial disease. The findings of this first Tasigna side effects study have been echoed in many studies since, originating from the U.S., Canada and Europe. In 2013 alone, nine different Tasigna atherosclerosis studies were published, including a review of literature from the FDA which found a strong connection between Tasigna and atherosclerosis."

[MWLE in reply to ElliotGreen]

For this purpose, dosage is usually 800+ mg. Don't know if there is a similar affect for lower dosage such as 150mg.

[jeffreyn]

See also this earlier discussion (about 5 months ago):

healthunlocked.com/parkinso...

[ElliotGreen in reply to jeffreyn]

And also this from 9 days ago. User tacato talks about participating in the latest study.

healthunlocked.com/parkinso...

[enjoysalud]

Hi, my son was first DX with Parkinson's (that's why I still haunt this site), 2015. He was later DX with PSP (Jan 2017), and died May 4, 2017.

Grafixapn who lives in Arizona. His wife has PSP. He has more than once posted on NILOTINIB and how he feels it is the only drug that is helping his wife. A neurologist in Arizona is trying to recruit those with PSP to try NILOTINIB.

You might want to contact him or at least refer him to this posting.

Margarita, Los Angeles, CA, USA (thank you for your "research" postings

[Erniediaz1018 in reply to enjoysalud]

Thank you Margarita

[LindaP50 in reply to enjoysalud]

Very sorry for your loss.

Thanks for your post.

[Farooqji]

Nilotinib costs $53.96 per pill (200 mg)

pharmacychecker.com/tasigna/

[ElliotGreen in reply to Farooqji]

Dayum.

[PDGal4]

Yes, this drug carries a 'black box warning'--risk of sudden death. Dr. Pagan, in charge of the Nilotinib trial at Georgetown Hosp, believes that because the dosage is lower than used for cancer treatment, the risk is much less. One of the criteria that eliminates people from the trial is long QT on their ECGs.

It does seem to hold great promise. Participants in the Georgetown trial, which is double blind, go off for 2 months after a year of receiving placebo or one of two dosages (can't recall at the moment what those are.) The drug stops working and symptoms come back when it is stopped, so I guess they are verifying that too. Then trial participants receive the drug--open--that is doctor and they know dosages they receive, for another year.

[ElliotGreen]

Here's the second nilotinib abstract from the 23rd world congress on PD and related disorders.

TITLE: A phase 2A study of nilotinib in patients with advanced and early Parkinson’s disease study design

AUTHORS: Simuni T. an 15 other authors

INSTITUTIONS: Northwestern University Feinberg School of Medicine, The Michael J Fox

Foundation, and several others

To assess the safety and tolerability of nilotinib (150-300 mg QD) in moderate/advanced and early/de novo Parkinson disease (PD) participants.

We have initiated a Phase 2a randomized, double-blind, placebo-controlled, parallel group, two cohort

study. See Figure 1 for study design. The study will enroll 75 participants with moderate to advanced PD in Cohort 1. The participants will be randomized 1:1:1 to a once daily dose of nilotinib or placebo (150 mg : 300 mg : placebo) for 6 months. Assuming one or more doses are determined to be safe in Cohort 1, Cohort 2 will enroll 60 de novo PD participants randomized 2:1 to a once daily dose of nilotinib or placebo (the highest tolerated and safe dose from cohort 1: placebo) for 12 months. The primary outcome for both cohorts is safety and tolerability. A key secondary objective for Cohort 1 is a futility analysis of the change in the MDS-UPDRS part III score, based on the magnitude of the change observed in the previously completed pilot study (ClinicalTrials.gov NCT02281474).

Additional secondary and exploratory outcomes include assessment of symptomatic effect of nilotinib; impact of nilotinib on progression of PD disability (MDS-UPDRS OFF/ON); cognitive function (DRS-2); and quality of life measures. The study also includes a comprehensive battery of serum and spinal fluid biomarkers, measures of serum pharmacokinetics and levels of nilotinib in cerebrospinal fluid.

The study is conducted at 25 Parkinson Study Group (PSG) sites in US. The first participant was recruited November 2017. Recruitment for Cohort 1 is expected to be completed in fall 2018, with follow-up continuing through late 2018.

This study will provide further information on safety/tolerability, dose selection and biomarkers profile of Nilotinib as a potential novel therapy to slow PD progression and determine if it is warranted to proceed with the future efficacy studies.

[ElliotGreen]

Here's a 2015 article critical of the hype surrounding Nilotinib after the initial Phase 1 clinical trial. One of the authors is the CEO of the Michael J Fox Foundation.

Nilotinib – Differentiating the Hope from the Hype.

ncbi.nlm.nih.gov/pmc/articl...

"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."