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miracleseeker

Nilotinib for PD and Lewy Body

15 posts in this topic

Dr. Okun,

 

I just read an article about using a very small dose of this drug that is used for Leukemia to treat PD and other neurological diseases. Supposedly it will clean out the bad protein build ups in the brain. Sounds like it's in the 2nd phase of the clinical trials. What do you think about this? Will it be a success and approved quickly for this purpose since it's already out in the market. I am very hopeful about this being that it's not something created out of thin air so we know it's safe at least for now.

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Here is the abstract from a recent paper on this compound. It is very interesting and we will have to see how it fares in clinical trials including the safety profile. It is unclear if compounds like this that may help clear bad protein will change the clinical course of PD. Hope this helps.

 

Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of a-synuclein in Parkinson's disease models

+Author Affiliations

 

Abstract

Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of a-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of a-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases a-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of a-synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of a-synuclein and hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in a-synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes. Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of a-synuclein, protection of SN neurons and amelioration of motor performance. These data suggest that nilotinib may be a therapeutic strategy to degrade a-synuclein in PD and other a-synucleinopathies.

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The most recent drug to be approved is IPX066 for PD-- a drug that is a combination of regular and long acting dopamine. It is currently in the labeling phase.

 

There are many ways to make PD animals. This can be done using genetics (knocking out a gene), or by giving a toxin (rotenone or MPTP for example). Many animal models show promise when testing drugs; but when tried in humans it cannot be replicated.

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Rytary is in the labeling stage? The last I read it is still being reviewed by the FDA and will be dropped by Glaxo in July before it's even out in the market.

If testing on animals does not replicate the same effects in humans then why do it at all?

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The last information I had was that it was progressing through the FDA, and that there were a few steps needed to be taken. Below outlines the changes from nasdaq.com and you are right that it is entirely possible it could be held up if these issues are not resolved.

 

 

Glaxo-Impax End Rytary Deal - Analyst Blog

 

By Zacks.com, April 30, 2013, 04:48:45 PM EDT

 

 

 

GlaxoSmithKline ( GSK ) and Impax Pharmaceuticalsicon1.png, the brand products division of Impax Laboratories, Inc. ( IPXL ), recently announced the termination of their agreement for Rytary (IPX066). Rytary is being developed for the symptomatic treatment of adults suffering from idiopathic Parkinson's disease.

 

We remind investorslb_icon1.png that in Dec 2010, Impax had entered into a license, development and commercialization agreement with Glaxo for Rytary. As per the terms of the agreement, Glaxo is responsible for the development and commercialization of the candidate outside the US and Taiwan.

 

Glaxo decided to return those rights to Impax, effectivelb_icon1.png end Jul 2013. Delays in regulatory approval and launch dates in countries that Glaxo has rights to led to the decision. Following Glaxo's decision, Impax will be responsible for the development of the candidate across the globe. The company will look for a partner in ex-US markets.

 

We see the withdrawal of Glaxo from the Rytary deal as a huge disappointment for Impax. In the US, the regulatory path for Rytary has been far from smooth. In Jan 2013, Impax received a major setback with the US Food and Drug Administration (FDA) issuing a complete response letter (CRL) for the marketing application for Rytary.

 

According to the CRL, the NDA may be approved only after a satisfactory re-inspection of Impax's Hayward facility for which a warning letter was issued in May 2011.The facility is involved in the development of Rytary. However, in Mar 2013, when the FDA completed its re-inspection of the company's manufacturingicon1.png facility at Hayward, it issued a new Form 483 with 12 observations. Impax is working diligently on the issues noted by the FDA and expects to resolve the matter quickly. However, the new Form 483 remains a major overhang on the stock.

 

Impax and Glaxo both currently carry a Zacks Rank #3 (Hold). Companies that currently look attractive include UCB ( UCBJF ) and Catalyst Pharmaceuticals Partners Inc. ( CPRX ). Both stocks carry a Zacks Rank #1 (Strong Buy).

 

 

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tick tock.... this drug seems to be cursed.

 

Please answer the 2nd question. Why do we test on animals when they results may not be the same for humans?

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Good question.

 

The FDA and most scientists prefer to test theories in animal models of disease and to try as best as possible to establish safety, dosing, and efficacy--all of which can guide human trials.

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The last I heard was that Georgetown NPF Center of Excellence was planning a trial.

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I am not sure but I have only heard about Parkinson and the possibility of ALS (nilotinib trial).  Best to keep checking clinicaltrials.gov

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Phase 1 of a trial of nilotinib for treating Lewy Body Dementia (LBD) reported at Neuroscience meeting last autumn (2015).  Although open label and small numbers, Pagan and Moussa did obtain encouraging results in surrogate markers, such as a drop in cerebrospinal fluid levels of alpha synuclein.  There were also anecdotes describing remarkable reversals of disease symptoms in some treated LBD patients.  Combined with the mouse results reported earlier, a logical mechanism of action, and confirmation of certain results published by a group at Johns Hopkins, I began donating directly to Moussa's phase II clinical trial, which is only enrolling patients at Georgetown.  My hope is to get a second site funded, hopefully in Los Angeles.  I even wrote to Novartis to point out that nilotinib will be a blockbuster if proven effective.  Of note, Dr. Moussa has filed patents for the treatment of neurodegenerative diseases with nilotinib, which is the only reason I can determine that might inhibit their investment in the clinical trial for Parkinson disease.  My question for Dr. Okun is why not do a quick and cheap futility study on nilotinib, which should be cheaper and faster than a full-blown series of clinical trials?  Even less expensive might be to track down any Parkinson patients treated with nilotinib for lymphoma or leukemia to see how their neurological symptoms fared.  Has this been done?

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Great idea, but in general these quick and dirty fast studies end up raising more questions than answers.  I think the Georgetown group is doing the right thing by organizing careful followup studies.

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