The biotech company Acorda Therapeutics Inc. yesterday announced that it was halting new recruitment for the phase III program of its drug Tozadenant (an oral adenosine A2a receptor antagonist).
In addition, participants currently enrolled in the trial will now have their blood monitoring conducted on a weekly basis.
The initial report looks really bad (tragically five people have died), but does this tragic news mean that the drug should be disregarded?
In todays post, we will look at what adenosine A2a receptor antagonists are, how they may help with Parkinson’s, and discuss what has happened with this particular trial.
Dr Ron Cohen, CEO of Acorda. Source: EndpointNews
Founded in 1995, Acorda Therapeutics Ltd is a biotechnology company that is focused on developing therapies that restore function and improve the lives of people with neurological disorders, particularly Parkinson’s disease.
Earlier this year, they had positive results in their phase III clinical trial of Inbrija (formerly known as CVT-301 – Click here to read a previous post about this). They have subsequently filed a New Drug Application with the US Food and Drug Administration (FDA) to make this inhalable form of L-dopa available in the clinic, but the application has been delayed due to manufacturing concerns from the FDA (Click here to read more about this). These issues should be solvable – the company and the FDA are working together on these matters – and the product will hopefully be available in the new year.
So what was the news yesterday?
Acorda Therapeutics has another experimental product going through the clinical trial process for Parkinson’s disease.
It’s called Tozadenant.
Tozadenant is an oral adenosine A2a receptor antagonist (and yes, we’ll discuss what all that means in a moment).
Yesterday Acorda Therapeutics Inc announced that they have halted new recruitment for their phase III clinical program. In addition the company is increasing the frequency of blood cell count monitoring (from monthly to weekly) for participants already enrolled in the company’s Phase 3 program of Tozadenant for Parkinson’s disease.
The Company took this action due to reports of cases of agranulocytosis.
Trehalose is a small molecule – nutritionally equivalent to glucose – that helps to prevent protein from aggregating (that is, clustering together in a bad way).
Parkinson’s disease is a neurodegenerative condition that is characterised by protein aggregating, or clustering together in a bad way.
Is anyone else thinking what I’m thinking?
In today’s post we will look at what trelahose is, review some of the research has been done in the context of Parkinson’s disease, and discuss how we should be thinking about assessing this molecule clinically.
Neuropathologists examining a section of brain tissue. Source: Imperial
When a neuropathologist makes an examination of the brain of a person who passed away with Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a definitively postmortem diagnosis of the condition:
1. The loss of dopamine producing neurons in a region of the brain called the substantia nigra.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
2. The clustering (or ‘aggregation’) of a protein called alpha synuclein. Specifically, they will be looking for dense circular aggregates of the protein within cells, which are referred to as Lewy bodies.
A Lewy body inside of a neuron. Source: Neuropathology-web
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
In addition to Lewy bodies, the neuropathologist may also see alpha synuclein clustering in other parts of affected cells. For example, aggregated alpha synuclein can be seen in the branches of cells (these clusterings are called ‘Lewy neurites‘ – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Given these two distinctive features of the Parkinsonian brain (the loss of dopamine neurons and the aggregation of alpha synuclein), a great deal of research has focused on A.) neuroprotective agents to protect the remaining dopamine-producing neurons in the substantia nigra, and B.) compounds that stop the aggregation of alpha synuclein.
In today’s post, we will look at the research that has been conducted on one particular compounds that appears to stop the aggregation of alpha synuclein.
It is call Trehalose (pronounces ‘tray-hellos’).
The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.
Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.
And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.
The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.
Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.
At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).
Reduction in motor scores in Exenatide group. Source: Lancet
This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.
In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:
So what is Exenatide?
This is Lysimachos.
Pronounced: “Leasing ma horse (without the R)” – his words not mine.
He is one of the founders of an Edinburgh-based biotech company called “Parkure“.
In today’s post, we’ll have a look at what the company is doing and what it could mean for Parkinson’s disease.
The first thing I asked Dr Lysimachos Zografos when we met was: “Are you crazy?”
Understand that I did not mean the question in a negative or offensive manner. I asked it in the same way people ask if Elon Musk is crazy for starting a company with the goal of ‘colonising Mars’.
In 2014, Lysimachos left a nice job in academic research to start a small biotech firm that would use flies to screen for drugs that could be used to treat Parkinson’s disease. An interesting idea, right? But a rather incredible undertaking when you consider the enormous resources of the competition: big pharmaceutical companies. No matter which way you look at this, it has the makings of a real David versus Goliath story.
But also understand this: when I asked him that question, there was a strong element of jealousy in my voice.
Incorporated in October 2014, this University of Edinburgh spin-out company has already had an interesting story. Here at the SoPD, we have been following their activities with interest for some time, and decided to write this post to make readers aware of them.