This week, biotech firm Prothena published the results of their Phase I safety and tolerance clinical trial of their immunotherapy treatment called PRX002 (also known as RG7935).
Immunotherapy is a method of artificially boosting the body’s immune system to better fight a particular disease.
PRX002 is a treatment that targets a toxic form of a protein called alpha synuclein – which is believed by many to be one of the main villains in Parkinson’s.
In today’s post, we will discuss what immunotherapy is, review the results of the clinical trial, and consider what immunotherapy could mean for the Parkinson’s community.
I have previously mentioned on this website that any ‘cure for Parkinson’s’ is going to require three components:
- A disease halting mechanism
- A neuroprotective agent
- Some form of cell replacement therapy
This week we got some interesting clinical news regarding the one of these components: A disease halting mechanism.
The Phase I results of a clinical trial being conducted by a company called Prothena suggest that a new immunotherapy approach in people with Parkinson’s is both safe and well tolerated over long periods of time.
The good folks at Prothena Therapeutics. Source: Prothena
What is immunotherapy?
This week Austrian biotech firm, AFFiRiS AG, made an announcement regarding their experimental immunotherapy/’vaccine’ approach for Parkinson’s.
In their press release, the company provided the results of a long-term Phase I clinical trial testing the tolerability and safety of their treatment AFFITOPE® PD01A.
The treatment was found to be safe and well-tolerated in people with Parkinson’s. But there was one sentence which was particularly intriguing in the press release regarding clinical symptoms.
In today’s post, we will discuss what is meant by ‘immunotherapy’, outline what this particular clinical trial involved, review the results, and explore what this could mean for the Parkinson’s community.
I have previously mentioned on this website that any ‘cure for Parkinson’s’ is going to require three components:
- A disease halting mechanism
- A neuroprotective agent
- Some form of cell replacement therapy
This week we got some interesting clinical news regarding the one of these components: A disease halting mechanism
Clinical trial results from Austria suggest that a new immunotherapy approach in people with Parkinson’s is both safe and well tolerated over long periods of time.
What is immunotherapy?
In a recent SoPD post, we discussed the importance of calcium and looked at how it interacts with the Parkinson’s-associated protein alpha synuclein, affecting the function and clustering of that protein.
During the writing of that post, another interesting research report was published on the same topic of calcium and alpha synuclein. It involved a different aspect of biology in the cell – a structure called the endoplasmic reticulum – but the findings of that study could also explain some aspects of Parkinson’s.
In today’s post, we will review the new research report, consider the biology behind the findings and how it could relate to Parkinson’s, and discuss how this new information could be used.
The original berserker. Source: Wikipedia
I can remember my father often saying “If you kids don’t be quiet, I’ll go berserk!”
Growing up, I never questioned the meaning of the word ‘berserk‘.
I simply took it as defining the state of mindless madness that my dad could potentially enter if we – his off-spring – pushed him a wee bit too far (and for the record, Dad actually ‘going berserk’ was a very rare event).
My father. But only on the odd occasion. Source: Screenrant
But now as I find myself repeating these same words to my own off-spring, I am left wondering what on Earth it actually means?
What is ‘berserk‘?
On this website, we regularly talk about a Parkinson’s-associated protein called Alpha Synuclein.
It is widely considered to be ‘public enemy #1’ in the world of Parkinson’s research, or at the very least one of the major ‘trouble makers’. It is a curious little protein – one of the most abundant proteins in your brain.
But did you know that there are different ‘species’ of alpha synuclein?
And recently researchers in Florida announced that they had identified an all new species of alpha synuclein that they have called “P-alpha-syn-star” or Pα-syn*.
In today’s post, we will discuss what is meant by the word ‘species’, look at the different species of alpha synuclein, and explore what this new species could mean for the Parkinson’s community.
This microscopic creature is called Macrobiotus shonaicus.
Isn’t it cute?
The researchers that discovered it found it in a Japanese parking lot.
It is one of the newest species of life discovered to date (Click here for the research report). It is a species of Tardigrade (meaning “slow stepper”; also known as a water bear or moss piglet). And for the uninitiated: Tardigrade are remarkable creatures.
Tardigrade. Source: BBC
They measure just 0.5 mm (0.02 in) long, there are approximately 1,150 known species of them, and they have been around for a VERY long time – with fossil records dating back to the Cambrian period (500 million years ago).
The tree of life (try and find the dinosaurs). Source: Evogeneao
But most importantly, tardigrade are EXTREMELY resilient:
- they are the first known animals to survive in hard vacuum and UV radiation of outer space. Some of them can withstand extreme cold – down to temperatures of −458 °F (−272 °C), while other species of Tardigrade can withstand extremely hot temperatures – up to 300 °F (150 °C) (Click here to read more)
- they can withstand 1,000 times more radiation than other animals (Click here for more on that)
- some species of Tardigrade can also withstand pressure of 6,000 atmospheres (that is nearly SIX times the pressure of water in the deepest ocean trench – the Mariana trench! Click here for more on this)
- They are one of the few groups of species that are capable of suspending their metabolism; surviving for more than 30 years at −20 °C (−4 °F – Click here to read about this)
They are utterly remarkable creatures.
Great, but what does this have to do with Parkinson’s? Continue reading
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
Recently I was invited to speak at the 6th Annual East Midlands Parkinson’s Research Support Network meeting at the Link Hotel, in Loughborough. The group is organised and run by the local Parkinson’s community and supported by Parkinson’s UK. It was a fantastic event and I was very grateful to the organisers for the invitation.
They kindly gave me two sessions (20 minutes each) which I divided into two talks: “Where we are now with Parkinson’s research?” and “Where we are going with Parkinson’s research?”. Since giving the talk, I have been asked by several attendees if I could make the slides available.
The slides from the first talk can be found by clicking here.
I have also made a video of the first talk with a commentary that I added afterwards. But be warned: my delivery of this second version of the talk is a bit dry. Apologies. It has none of my usual dynamic charm or energetic charisma. Who knew that talking into a dictaphone could leave one sounding so flat.
Anyways, here is the talk – enjoy!
I hope you find it interesting. When I have time I’ll post the second talk.
Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.
Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.
But it is not the only protein that may be playing a role in Parkinson’s.
Today’s post is all about TAU.
I recently informed my wife that I was thinking of converting to Taoism.
She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.
When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).
This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).
But I am genuinely curious about Taoism.
Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.
Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.
According to Taoism, salvation comes from just one source: Following the Tao.
Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).
My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.
You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.
What is TAU?
This is one of the first immuno-therapies being tested in Parkinson’s disease, and the results indicate that the treatment was active and well tolerated.
In this post we will review the press release and what it tells us regarding this clinical trial.
Antibodies binding to proteins. Source: AXS
When your body is infected by a foreign agent, it begins to produce some things called antibodies. In most cases, these are Y-shaped proteins that binds to the un-wanted invader and act as a beacon for the immune system. It is a very effective system, allowing us to go about our daily business without getting sick on a regular basis. Antibodies allow us to build up immunity, or resistance of an organism to infection or disease.
Scientist have harnessed the power of this natural process, and they have use it to develop methods of helping our bodies fight off disease.
The first approach is called Acquired Immunity (or adaptive immunity), and it is based on the idea that exposure of the immune system to a pathogen (disease/damage causing agent) creates an ‘immunological memory’ within our immune system, and this leads to an enhanced response to subsequent future encounters with that same pathogen.
Scientists have used the idea of acquired immunity to develop what we call vaccines – which are simply small, neutral fragments of specific pathogen that help the immune system to build up immunity (or resistance) before the body is attacked by the disease-causing pathogen itself.
Vaccination. Source: WebMD
The second approach is called Passive Immunity.
Passive immunisation is simply the sharing of antibodies. And that might sound a bit disturbing, but it is actually a naturally occurring process. For example, a mother’s antibodies are transferred to her baby in the womb via the placenta.
And again, scientists have devised ways of producing passive immunisation artificially. And recently researchers have been using this approach to attack many medical conditions (particularly cancer), in an area of medicine called immunotherapy.
Think of it as simply boosting the immune system by supplementing the supply of antibodies. Scientists can produce high levels of antibodies that specifically target a particular pathogen and then transfer those antibodies to affected people via an intravenous injection.
How is this being used for Parkinson’s disease?
Well, we have previously discussed the idea of a vaccine for Parkinson’s disease (click here to read that post), and we have been closely following the progress of an Austrian company, AffiRis, who are leading the vaccination approach (Click here for that post).
The vaccine approach is targeting the Parkinson’s disease associated protein, Alpha synuclein. It is believed that a bad kind of alpha synuclein is causing the spread of the condition, by being passed from cell to cell. The goal of the vaccine is to capture and remove all of the alpha synuclein being passed between cells and thus (hopefully) halt the progress of – or at least slow down – the disease.
And this week, another company – Prothena – has reported the results of their phase 1 trial for a passive immunity approach to Parkinson’s disease. They have been injecting subjects in the trial with a treatment called PRX002.
(Remember that a phase 1 trial simply tests the safety of a treatment in humans, it is not required to test efficacy of the treatment. Efficacy comes with phases 2 & 3 trials)
What is PRX002?
PRX002 is a monoclonal antibody. The scientists at the biotech company Prothena have artificially produced large amounts of antibodies to alpha synuclein and these have been injected into people with Parkinson’s disease.
Monoclonal antibodies. Source: Astrazeneca
Prothena provide a short video explaining this concept (click here to view the video).
So what were the results of the Prothena study?
The study was conducted in collaboration the pharmaceutical company Roche. It was a double-blind (so both the researchers and subjects did not know what they were receiving until the conclusion of the study), placebo-controlled study involving 80 people with Parkinson’s disease. The subjects were randomly assigned to one of six groups, which received either PRX002 or a placebo. There were six doses of PRX002 tested in the study (0.3, 1, 3, 10, 30 or 60 mg/kg).
The study was conducted over six-month, during which patients received three once-a-month injections of either PRX002 or placebo. The subjects were then followed for an observational period of three months.
According to the press release, no serious treatment-related adverse events were reported in PRX002 treated patients. Mild treatment-related adverse events (greater than anything experienced within the placebo group) were noted in 4 of the 12 subjects in the highest dosage group of PRX002, including constipation and diarrhoea.
Importantly, the investigators reported that thePRX002 antibodies were crossing the blood brain barrier and entering the brain. This resulted in a rapid reduction of alpha-synuclein levels (in some cases by up to 97 percent after a single dose!).
The follow-on Phase 2 clinical study is expected to begin in 2017.
What is the difference between the vaccine and the passive immunity approaches?
Basically, it comes down to levels of control. With a vaccination, once you have injected the vaccine and the immune system is activated, there isn’t much you can do to control the response of the body. And that immune memory is going to last a long time. The passive immunity response, on the other hand, requires regular injections of antibodies which can be stopped if adverse effects are noted.
Plus – and forgive me if I sound a little bit cynical here – drug companies prefer a regular treatment approach (which they can charge for each visit) compared to a one-shot cure. It’s simply a better business model.
What happens next?
In both cases – the vaccine and the passive immunity approaches – phase 2 trials are being set up by the respective companies and we will wait to see have affective these treatments are at slowing down Parkinson’s disease.
If they are affective, expect big headlines in the media and plans for adults everywhere to start being vaccinated. If they fail,…. well, we will have to re-address our understanding of the role of alpha synuclein in Parkinson’s disease.
Interesting times lie ahead.
The banner for todays post was sourced from Prothena
Exciting results published this week regarding a small phase 1b clinical trial of a new treatment for Alzheimer’s disease. In this post, we shall review the findings of the study and consider what they may mean for Parkinson’s disease.
An Alzheimer’s brain scans on the left, compared to a normal brain (right). Source: MedicalExpress
Alzheimer’s disease is the most common neurodegenerative disease, accounting for 60% to 70% of all cases of dementia. It is a progressive neurodegenerative condition, like Parkinson’s disease, affecting approximately 30 million people around the world.
Inside the brain, in addition to cellular loss, Alzheimer’s is characterised by the increasing presence of two features:
- Neurofibrillary tangles
- Amyloid plaques
A schematic demonstrating the difference between healthy and Alzheimer’s affected brains. Source: MmcNeuro
The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.
Amyloid plaques are clusters of proteins that outside the cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.
The releasing of Beta-Amyloid. Source: Wikimedia
Beta-amyloid is a very “sticky” protein and it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease. Thus, for a long time scientists have attempted to reduce the amount of free-floating beta-amyloid in the brain. One of the main ways they do this is with antibodies.
What are antibodies?
An antibody is the foundation of our immune system. It is a Y-shaped structure, that is used to alert the body when a foreign or unhealthy agent is present.
An artist’s impression of a Y-shaped antibody. Source: Medimmune
Two arms off the Y-shaped antibody have what is called ‘Antigen binding sites‘. An antigen is a molecule that is capable of inducing a response from the immune system (usually a foreign agent, but it can be a sick/dying cell).
A schematic representation of an antibody. Source: Wikipedia
There are currently billions of antibodies in your body -each with specific sets of antigen binding sites – awaiting the presence of their antigen. Antibodies are present in two forms: secreted, free floating antibodies, and membrane-bound antibodies. Secreted antibodies are produced by B-cells, which are part of the immune system. And it’s this secreted form of antibody that modern science has used to produce new medicines.
Really? How does that work?
Scientists can make antibodies in the lab that target specific proteins and then inject those antibodies into a patient’s body and trick the immune system into removing that particular protein. This can be very tricky, and one has to be absolutely sure of the design of the antibody because you do not want any ‘off-target’ effects – the immune system removing a protein that looks very similar to the one you are actually targeting.
These manufactured antibodies are used in many different areas of medicine, particularly cancer (over 40 antibody preparations have been approved by the U.S. Food and Drug Administration for use in humans against cancers). Recently, large pharmaceutical companies (like Biogen) have been attempting to use these manufactured antibodies against other conditions, like Alzheimer’s disease.
Which brings us to the study published this week:
Title: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.
Authors: Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A.
Journal: Nature. 2016 Aug 31;537(7618):50-6.
In this study, the researcher conducted a 12-month, double-blind, placebo-controlled trial of the antibody Aducanumab. This antibody specifically binds to potentially harmful beta-amyloid aggregates (both small and large). At the very start of the trial, each participants was given a brain scan which allowed the researchers to determine the baseline level of beta-amyloid in the brains of the subjects.
All together the study involved 165 people, randomly divided into five different groups: 4 groups received the 4 different concentrations of the drug (1, 3, 6 or 10 mg per kg) and 1 group which received a placebo treatment. Of these, 125 people completed the study which was 12 months long. Each month they received an injection of the respective treatment (remember these are manufactured antibodies, the body can’t make this particular antibody so it has to be repeated injected).
After 12 months of treatment, the subjects in the 3, 6 and 10 mg per kg groups exhibited a significant reduction in the levels of beta-amyloid protein in the brain (according to brain scan images), indicating that Aducanumab – the injected antibody – was doing it’s job. Individuals who received the highest doses of Aducanumab had the biggest reductions in beta-amyloid in the brain. Interestingly, this reduction in beta-amyloid in the brain was accompanied by a slowing of the clinical decline as measured by tests of dementia. Individuals treated with the placebo saw neither any reduction in their brain levels of beta amyloid nor their clinical decline.
The authors considered this study strong justification for larger phase III trials. Two of them are now in progress, with completion dates expected around 2020.
So this is a good thing right?
Yes, this is a very exciting result for the Alzheimer’s community. But the results must be taken with a grain of salt. We have discussed beta-amyloid in a previous post (Click here for that post). While it has long been considered the bad boy of the Alzheimer’s world, the function of beta-amyloid remains the subject of debate. Some researchers worry about the medical removal of it from the brain, especially if it has positive functions like anti-microbial (or disease fighting) properties.
Given that the treatment is given monthly and can thus be controlled, we can sleep easy knowing that disaster won’t befall the patients receiving the antibody. And if they continue to demonstrate a slowing/halting of the disease, it would represent a MASSIVE step forward in the neurodegenerative field. I guess what I am saying is that it is too soon to say. It will be interesting, however, to see what happens as these patients are followed up over time. And the two phase 3 clinical trials currently ongoing, which involve hundreds of participants, will provide a more definitive idea of how well the treatment is working.
So what does this have to do with Parkinson’s disease?
Yeah, so let’s get back to our area of interest: Parkinson’s disease. Biogen is the pharmaceutical company that makes the Alzheimer’s antibody (Aducanumab) discussed above. Biogen is also currently conducting a phase 1 safety trial (on normal healthy adults) of an antibody that targets the Parkinson’s disease associated protein, alpha synuclein. We are currently waiting to hear the results of that trial.
Several other companies have antibody-based approaches for Parkinson’s disease (all of them targeting the protein alpha synuclein). These companies include:
- Prothena – which completed phase 1 safety trials in March 2015 (Click here for more)
- Neuropore – which also completed phase 1 safety trials in March 2015 (Click here for more)
There are some worries regarding this approach, however. For example, alpha synuclein is highly expressed in red blood cells, and some researchers worry about what affects the antibodies may have on their function. In addition, alpha synuclein has been suspected of having anti-viral properties – reducing viruses ability to infect a cell and replicate (click here to read more on this). Thus, removal of alpha synuclein by injecting antibodies may not necessarily be a good thing for the brain’s defense system.
Unlike beta-amyloid, however, most of alpha synuclein’s activities seem to be conducted within the walls of brain cells, where antibodies can’t touch it. Thus the hope is that the only alpha synuclein being affected by the antibody treatment is the variety that is free floating around the brain.
The results of the Alzheimer’s study are a tremendous boost to the antibody approach to treating neurodegenerative diseases and it will be very interesting to watch how this plays out for Parkinson’s disease in the near future.
Watch this space!
The banner for today’s post was sourced from TheNewsHerald