Tagged: lysosome

Nilotinib: the other phase II trial

DSK_4634s

In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.

What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.

Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.

In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the  ongoing Georgetown Phase II trial.


FDA-deeming-regulations

The FDA. Source: Vaporb2b

This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.

This is exciting and welcomed news.

What is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).

What does any that mean?

Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.

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Cleaning up with Ambroxol

Exciting news recently with the announcement of the Ambroxol study starting.

Exciting for two reasons:

  1. Ambroxol has the potential to make a major impact in the lives of some people with Parkinson’s disease.
  2. It illustrates how FAST things are moving in the world of Parkinson’s disease!

 

Inside each and every cell, there are millions of tiny actions taking place. Minute processes all working in a collective manner allowing the cell to function normally. There are lots of proteins helping to make other proteins, lots of proteins helping other proteins to get to where they need to be, and lots of proteins helping to break down other proteins after they have done their job.

All this activity generates a lot of waste. And a fundamental part of the activity in any cell is waste disposal. If that does not function properly, the cell is in serious trouble.

One of the most common genetic mutations associated with Parkinson’s disease – called GBA – results in cells having trouble getting rid of waste.

GBA-cartoon

Adapted from a cartoon by Dr Jing Pu. Source: The Nichd connection

What is GBA?

Glucocerebrosidase (or GBA) is an enzyme that helps with the recycling of waste. It is active in inside ‘lysosomes‘.

What are Lysosomes?

Lysosomes are small structures inside cells that act like recycling centers. Waste gets put inside the lysosome where enzymes like GBA help to break it down into useful parts. Mutations in the GBA gene can result in an abnormally short, non-functioning version of the enzyme. And in those cases the breaking down of waste inside the lysosome because inhibited.

What is the connection between GBA and Parkinson’s disease?

GBA mutations are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene are at higher risk of developing Parkinson’s disease than the general population. And people with Parkinson’s are approximately five times more likely to carry a GBA mutation than healthy control subjects.

So what is Ambroxol?

Ambroxol is a commonly used treatment for respiratory diseases. It promotes mucus clearance and eases coughing. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ok, but why the excitement for Parkinson’s disease?

In May of 2014 – less than 2 years ago – this study was published:

McNeil1

Title: Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells.
Authors: McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH.
Journal: Brain. 2014 May;137(Pt 5):1481-95.
PMID: 24574503    (This report is OPEN ACCESS if you want to read it)

It was the first time that Ambroxol – a commercially available drug – had been tested in a Parkinson’s disease related context.

In this study the researchers collected skin cells (called fibroblasts) from eleven people with GBA mutations (some had been diagnosed with Parkinson’s disease). They measured the amount of glucocerebrosidase protein and enzyme activity in these cells, and they found that glucocerebrosidase enzyme activity was significantly reduced in fibroblasts from GBA mutations (on average just the enzyme was acting at just 5% of normal levels). They found that ambroxol increased glucosylceramidase activity in fibroblasts from people with GBA mutations AND in fibroblasts from healthy controls. Ambroxol treatment also reduced markers of oxidative stress in GBA mutant cells.

Given the increase in glucocerebrosidase activity after ambroxol treatment, the researchers wondered whether the drug would reduce alpha-synuclein levels in cells that were over-expressing this protein. Amazingly, after 5 days of ambroxol treatment, levels of alpha-synuclein had decreased significantly (15% on average 15%).

You can understand why the researchers were a little bit excited by these results. Here was a drug that re-activated the recycling unit in the cell and reduced levels of one of the main proteins associated with Parkinson’s disease. If the drug can reduce the levels of alpha synuclein in the brains of people with Parkinson’s disease, maybe the researchers will be able to slow down (or even halt) the disease!

Additional studies have now been reported which have confirmed the initial results.

And now the clinical trial?

Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), it was announced this week that they had started recruiting subjects to be involved in a clinical trial at the Royal Free Hospital in London. The trial is a phase 1 study which will test the safety of Ambroxol in Parkinson’s disease. The researchers will also look to see if Ambroxol can increase levels of glucocerebrosidase and whether this has any beneficial effects in the subjects. The study will be conducted on 20 people with Parkinson’s disease who also have GBA mutations. They will be given the drug and followed over the next 24 months.

These are exciting times for the world of Parkinson’s disease as these drugs are no longer simply reducing the motor features of the condition, but actually attempting to slow/halt the disease.

And as we suggested at the start of the post the pace of these developments is becoming hard to keep up with.