Tagged: Phase 3

An exercise in expectations: Exenatide III

 

In August 2017, the results of a Phase II double-blind, placebo controlled clinical trial investigating whether the diabetes drug Exenatide (aka Bydureon) can be repurposed for the treatment of Parkinson’s were published.

Despite the fact that the study did not meet most of its end points, the Parkinson’s community got very excited about one of the results: The exenatide treated group demonstrated a stabilisation of their motor features over the 48 week trial, while the control group continued to worsen.

Over night, for many in the community, the hypothetical (a “disease-halting medication”) suddenly become a possibility. After such a long trail of negative clinical trial results, it was a very human and natural response for everyone to get excited. But with the news this month, that the Phase III exenatide clinical trial is about to start, the community needs to curb that excitement in order for a proper evaluation of the drug to take place.

In today’s post, we will look at the details of the new Phase III clinical trial for Exenatide and discuss why it is important to manage expections.

 


 

Here on the SoPD website we are often discussing novel potentially disease modifying therapies for Parkinson’s. And it is rather staggering the number and range of different approaches currently being tested on Parkinson’s.

And I am often asked, “Simon, if you were a betting man, which one I would put my money on? Which one are you expecting to work?

Now, before we go on dear reader, please understand that my answer to this question will problably disappoint you.

You see, I do not expect any of these experimental treatments being clinically tested to work.

WHAT THE?!?

Now, before you turn off, please let me explain – because this is important (it is not click-bait).

Ok, I’m listening. Why don’t you expect any of these treatments to work?!?

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Clinical trials: Trying to make them SEAMless

 

The clinical testing new compounds is horrifically slow. There is simply no easy way to word it. From lab bench to regulator approval, we are currently looking at a process which will take at least a decade.

The repurposing of clinically available treatments has shortened this process, but there are a limited number of drugs that can be repurposed, and the periods of time between clinical trials is still too long.

Acknowledging this situation, we can do one of two things: Accept the circumstances and carry on doing things the way we have always done it (hoping that it will be different next time – a la Einstein’s definition of insanity),… OR we can try to change it.

In today’s post, we will discuss an interesting project that is seeking to do the latter.

 


The guy at the podium (and in the upper left inset) is Barry Chandler.

A few months ago, Barry came to me and asked “What can I do to help?

And I replied by asking “What do you do?

Two things you need to know about Barry:

  1. He was diagnosed with young onset Parkinson’s 6 years ago, and
  2. He is a very well connected guy.

VERY well connected!

I am the green string. Barry is everything else. Source: Philiphemme

By day, Barry works in the city of London as a DevOps practitioner (that was a new one for me too – “a combination of cultural philosophies, practices, and tools that increases an organization’s ability to deliver applications and services at high velocity“). But in the evenings and on weekends, Barry is an events co-ordinator.

And these two worlds merge nicely in the form of a meetup group that Barry runs, called “SEAM”.

What is SEAM?

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Exciting Exenatide Exosomes

 

Recent analysis of blood samples collected during the Phase II clinical trial of Exenatide in Parkinson’s has uncovered a very interesting finding that could have major implications for not only Parkinson’s, but for many different neurological conditions.

Exenatide is a treatment that helps to control glucose levels in people with diabetes. More recently, however, it has been suggested that this drug may also have beneficial effects in Parkinson’s. A collection of clinical trials in Parkinson’s are currently unway to test this idea.

The researchers who conducted a Phase II clinical trial of Exenatide in Parkinson’s have analysed ‘exosomes‘ collected from the blood of participants, and they found something rather remarkable.

In today’s post we will discuss what exosomes are, what the researchers found, and why their discovery could have major implications for all of neurological research.

 


 

Here on the SoPD website we have discussed at length the Phase II clinical trial of Exenatide in Parkinson’s (Click here, here and here to read more about this).

This week, however, researchers involved in the study reported yet another really interesting finding from the trial. And this one could have profound consequences for how we study not only Parkinson’s, but many other neurological conditions.

What did they find?

Last week this report was published:

Title: Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial.
Authors: Athauda D, Gulyani S, Karnati H, Li Y, Tweedie D, Mustapic M, Chawla S, Chowdhury K, Skene SS, Greig NH, Kapogiannis D, Foltynie T.
Journal: JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4304. [Epub ahead of print]
PMID: 30640362

In the Exenatide Phase II clinical trial, 60 people with moderate Parkinson’s were randomly assigned to receive either 2mg of Exenatide or placebo once weekly for 48 weeks followed by a 12-week washout (no treatment) period. The results suggested a stablisation of motor features over the 48 weeks of the study in the treated group (while the condition in the placebo group continued to progress).

During the study (which was conducted between June 2014 – June 2016), blood samples were collected at each assessement.

From those blood samples, serum was collected and analysed.

Remind me again, what is serum?

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Busy day for Parkinson’s – 9/2/2017

 

o-busy-facebook

Today there was a lot of Parkinson’s related activity in the news… well, more than usual at least.

Overnight there was the publication of a blood test for Parkinson’s disease, which looks very sensitive. And this afternoon, Acorda Therapeutics announced positive data for their phase three trial.

In this post, we’ll look at what it all means.


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Blood cells. Source: Reference.com

Today we found out about an interesting new study from scientists at Lund University (Sweden), where they are developing a test that can differentiate between different types of Parkinsonisms (See our last post about this) using a simple blood test.

We have previously reported about an Australian research group working on a blood test for Parkinson’s disease, but they had not determined whether their test could differentiate between different kinds of neurodegenerative conditions (such as Alzheimer’s disease). And this is where the Swedish study has gone one step further…

blood
Title: Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder
Authors: Hansson O, Janelidze S, Hall S, Magdalinou N,  Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K, & For the Swedish BioFINDER study
Journal: Neurology, Published online before print February 8, 2017
PMID: N/A       (This article is OPEN ACCESS if you would like to read it)

The research group in Lund had previously demonstrated that they could differentiate between people with Parkinson’s disease and other types of Parkinsonism to an accuracy of 93% (Click here to read more on this). That is a pretty impressive success rate – equal to basic clinical diagnostic success rates (click here for more on this).

The difference was demonstrated in the levels of a particular protein, neurofilament light chain (or Nfl). NfL is a scaffolding protein, important to the cytoskeleton of neurons. Thus when cells die and break up, Nfl could be released. This would explain the rise in Nfl following injury to the brain. Other groups (in Germany and Switzerland) have  also recently published data suggesting that Nfl could be a good biomarker of disease progression (Click here to read more on this).

There was just one problem: that success rate we were talking about above, it required cerebrospinal fluid. That’s the liquid surrounding your brain and spinal cord, which can only be accessed via a lumbar puncture – a painful and difficult to perform procedure.

lumbar-puncture-cropped

Lumbar puncture. Source: Lymphomas Assoc.

Not a popular idea.

This led the Swedish researchers to test a more user friendly approach: blood.

In the current study, the researchers took blood samples from three sets of subjects:

  • A Lund set (278 people, including 171 people with Parkinson’s disease (PD), 30 people with Multiple system atrophy (MSA), 19 people with Progressive Supranuclear Palsy (PSP), 5 people with corticobasal syndrome (CBS), and 53 people who were neurologically healthy (controls).
  • A London set (117 people, including 20 people with PD, 30 people with MSA, 29 people with PSP, 12 people with CBS, and 26 neurologically healthy controls
  • An early disease set (109 people, including 53 people with PD, 28 people with MSA, 22 people with PSP, 6 people with CBS). All of the early disease set had a disease duration less than 3 years.

When the researchers looked at the levels of NfL in blood, they found that they could distinguish between people with PD and people with PSP, MSA, and CBS with an accuracy of 80-90% – again a very impressive number!

One curious aspect of this finding, however, is that the levels of Nfl in people with PD are very similar to controls. So while this protein could be used to differentiate between PD and other Parkinsonisms, it may not be a great diagnostic aid for determining PD verses non-PD/healthy control.

In addition, what could the difference in levels of Nfl between PD and other Parkinsonisms tell us about the diseases themselves? Does PD have less cell death, or a more controlled and orderly cell death (such as apoptosis) than the other Parkinsonisms? These are questions that can be examined in follow up work.


but-wait

Source: 3rd-Solutions

Like we said at the top, it’s been a busy day for Parkinson’s disease: Good news today for Acorda Therapeutics, Inc.

acordatherapeuticslogo_calogo2306

Source: Acorda

They announced positive Phase 3 clinical trial results for their inhalable L-dopa treatment, called CVT-301, which demonstrated a statistically significant improvement in motor function in people with Parkinson’s disease experiencing OFF periods.

We have previously discussed the technology and the idea behind this approach to treating Parkinson’s disease (Click here for that post).

levodopa-inhaler-lead-658x394

The ARCUS inhalation technology. Source: ParkinsonsLife

Basically, the inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs. The lungs allow for quicker access to the blood system and thus, the L-dopa can get to the brain faster. This approach will be particularly useful for people with Parkinson’s disease who have trouble swallowing pills/tablets – a common issue.

The Phase 3, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of CVT-301 when compared with a placebo in people with Parkinson’s disease who experience motor fluctuations (OFF periods). There were a total of 339 study participants, who were randomised and received either CVT-301 or placebo. Participants self-administered the treatment (up to five times daily) for 12 weeks.

The results were determined by assessment of motor score, as measured by the unified Parkinson’s disease rating scale III (UPDRS III) which measures Parkinson’s motor impairment. The primary endpoint of the study was the amount of change in UPDRS motor score at Week 12 at 30 minutes post-treatment. The change in score for CVT-301 was -9.83 compared to -5.91 for placebo (p=0.009). A negative score indicates an improvement in overall motor ability, suggesting that CVT-301 significantly improved motor score.

The company will next release 12-month data from these studies in the next few months, and then plans to file a New Drug Application (NDA) with the Food and Drug Administration (FDA) in the United States by the middle of the year and file a Marketing Authorization Application (MAA) in Europe by the end of 2017. This timeline will depend on some long-term safety studies – the amount of L-dopa used in these inhalers is very high and the company needs to be sure that this is not having any adverse effects.

All going well we will see the L-dopa inhaler reaching the clinic soon.


 

The banner for today’s post was sourced from the Huffington Post