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.
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
Interest press release from the biotech company AFFiRiS last week (Click here for the press release) regarding their clinical trial of a vaccine for Parkinson’s disease. We have previously outlined the idea behind the trial (Click here for that post) and the team at Michael J Fox foundation also provide a great overview (Click here for that – MJF are partly funding the trial). In today’s post we will briefly review what results AFFiRiS has shared.
Vaccination. Source: WebMD
Vaccination represents an efficient way of boosting the immune system in the targeting of foreign or problematic agents in the body. For a long time it has been believed that the protein Alpha Synuclein is the ‘problematic agent’ involved in the spread of Parkinson’s disease inside the brain. Alpha synuclein is required inside brain cells for various normal functions. In Parkinson’s disease, however, this protein aggregates for some reason and forms circular clusters inside cells called Lewy bodies.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
It has been hypothesized (and there is a lot of experimental evidence available to support the idea) that released alpha synuclein – freely floating between brain cells – may be one method by which Parkinson’s disease spread through the brain. With this in mind, groups of scientists (like those at AFFiRiS) are attempting to halt the spread of the condition, by training the immune system to target free-floating alpha synuclein. Vaccination is one method by which this is being attempted.
AFFiRiS is a small biotech company in Vienna (Austria) that has an ongoing clinical trial program for a vaccine (called ‘AFFITOPE® PD01A’) against alpha synuclein. The subjects in the study (22 people with Parkinson’s disease) received four vaccinations – each injection given four-weeks apart – and then the subjects were observed for 2-3 years (6 additional subjects were included in the study for comparative sake, but they did not receive the vaccine.
Last week the company issued a press release regarding a phase 1 trial (AFF008), which indicated that PD01A is safe and well tolerated, and causing an immune response (which is a good thing) in 19 of 22 (86%) of vaccinated subjects. In 12 of those 19 (63%) participants with and immune response, the researchers found alpha-synuclein antibodies in the blood, suggesting that the body was reacting to the injected vaccine and producing antibodies against alpha synuclein (for more on what antibodies are, click here).
The scientists also conducted some exploratory efficacy assessments – to determine if they could see if the vaccine was working clinically and slowing down the disease. Eight of the 19 (42%) subjects with an immune response, had no increase of their dopaminergic medication (eg. L-Dopa) over the course of the observational period (average three years per subject). And five of those eight subjects had stable clinical motor scores at the end of the study.
The company also conducted parallel laboratory-based experiments which indicate that AFFITOPE® PD01A-induced antibodies are binding to alpha-synuclein in various models of Parkinson’s disease.
The company will be presenting the results on a poster at the 4th World Parkinson Congress in Portland, Oregon, USA on September 21.
So this is a good result right?
It is easy to get excited by the results announced in the press release, but they must be taken with a grain of salt. This is a Phase I trial which is only designed to test the safety of a new therapeutic agent in humans. From this point of view: Yes, the study produced a good result – the vaccine was well tolerated by the trial subjects.
Drawing any other conclusions, however, is not really possible – the study was not double-blind and the assignment of subjects to the treatment groups was not randomize. In addition, the small sample size makes it very difficult to make any definitive conclusions. It must be noted that of the 22 people with Parkinson’s disease that started the study, only five exhibited stabilized clinical motor scores at the end of the study. It may be too soon to tell if the vaccine is having an effect in most of the people involved in the study. Thus longer observation periods are required – which the company is currently undertaking with their follow-up study, AFF008AA. The results of that study are expected in middle-late 2017.
We shall keep you posted.
The banner for today’s post was sourced from AFFiRiS
There has never been a more exciting time in Parkinson’s disease research. At no point in the past has the progress been made at such a frenetic pace. New week, new discoveries. And it has to be said that none of this would be possible without the advocacy and fundraising efforts of groups such as the Michael J Fox foundation, the Cure PD Trust, and Parkinson’s UK.
In addition to learning a great deal about the basic science of Parkinson’s disease – a better understanding of the biology underlying the disease – we are also making tremendous gains in new areas of treatment. Until now, the basic treatment has been dopamine replacement with L-dopa. But now, like never before, novel therapeutic approaches are being tested in the clinic.
One of these new approaches, however, is based on a very old idea: Vaccination.
Edward Jenner (1749 – 1823). Source: Wikipedia
While Edward Jenner is considered to be the pioneer of the world’s first vaccine (for Smallpox), the idea of vaccination/inoculation actually originated in India in 1000 BC, where it was briefly mentioned in Sact’eya Grantham, an Ayurvedic text. The first really credible mention of inoculation, however, was in China where it was described in the book Yuyi cao (寓意草 or Notes on My Judgment) by Yu Chang, published in 1643.
Vaccination. Source: WebMD
The basic idea of vaccination is to deliberately introduce an individual to a small component of a disease-causing agent so that the body can build up an immune response to the disease prior to being attacked by the full disease. That fragment of the disease-causing agent becomes what is known as an an ‘antigen’ (this comes from a French word, antigène, derived from the Greek anti- or “against”, and the word-forming suffix -gen, “thing that produces or causes”), and it will serve as the target for the immune system. In response to the antigen, the body produces beacons that bind to the antigen for the immune system to look out for – these beacons are called ‘antibodies’, and they tell the immune system that what they have bound to is ‘not of this body – get rid of it’!
Vaccines will sometimes be made of an empty virus – the surface of the virus will be present, but the internal disease-causing mechanisms have been destroyed or removed. Think of it as training the immune system for some big event. In this way, by exposing and thus priming the body against a particular part of s disease-causing agent, if the body is ever attacked by the full agent, the immune system will be ready to deal with it.
So what does this have to do with Parkinson’s disease?
The AFFiRiS drug (called PD01A in the AFF008 trial) is an vaccine that targets the Parkinson’s disease-related protein ‘Alpha-synuclein’. The vaccine causes the body to produce Alpha-synuclein-specific antibodies. These antibodies allow the immune system to then attack and remove this protein from the blood and fluid surrounding the brain. Any loose alpha-synuclein floating around should be removed.
Alpha-synuclein is a very common protein in the brain – it makes up about 1% of the material in neurons. It is also one of the proteins that is present in the ‘Lewy bodies’ that are associated with Parkinson’s disease.
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
Lewy bodies are one of the defining characteristic features of the Parkinsonian brain (having said that, it is interesting to note that approx. 30% of the population over the age of 70 will have Lewy bodies but no clinical symptoms/problems). They are densely packed, spherical shaped, clusters of protein inside the cell body. We are not entirely sure if they are causing cells to die, but they should not be there so it is assumed that if we get rid of them, the cells will be healthier.
An actual photo of a Lewy body (brown) within a neuron. Source: Medicalia
Given that Alpha-synuclein is one of the major components of Lewy bodies, it is the first protein to be targeted by a vaccine for Parkinson’s disease. Some researchers believe that the passing of Alpha synuclein from one cell to another may be the mechanism by which the disease spreads. By removing any Alpha-synuclein that floating around outside of cells, companies like Affiris hope that they will be able to slow down or even halt the spread of Parkinson’s disease within the brain.
The results from the first Affiris trial look rather promising.
The phase one trial run by Affiris was very small (just 12 subjects received the vaccine) and lasted only 12 months. The primary endpoint of any phase one trial is ‘safety and tolerability’ – that is to say, the study is a test of whether the drug is ok for humans use and can be well tolerated (e.g. it has no hidden/unknown side effects). Two different doses of the PD01A vaccine were given in the study and both were well tolerated by the participants in the study.
The Affiris researchers, however, were also looking at a second endpoint in their trial: whether the vaccine caused Alpha Synuclein-specific antibodies to be produced. Thankfully, Affiris found measurable levels of alpha-synuclein-specific antibodies in serum samples (a component of blood) and cerebrospinal fluid (the liquid surrounding the brain) collected from their participants, suggesting that the vaccine is doing it’s job and causing the immune system to react to the antigen being introduced.
Obviously a larger study is now required to determine if the vaccine will actually slow or halt Parkinson’s disease, but when the Affiris researchers compared the subjects in their first trial that received the vaccine with a group of control subjects at the end of the 12 months, they claim that they found PD01A subjects ‘functionally stabilised compared to the control group’.
And Affiris is not the only biotech company trialling the vaccine approach for Parkinson’s disease. In March 2015, an Irish company called ‘Prothena‘ announced that their vaccine reduced Alpha synuclein levels in the serum by 96%! And again the vaccine was well tolerated, with few side effects. 40 subjects were used in the Prothena study and the company will continue to follow them. They expect to release follow-up data – with clinical and imaging results – in early to mid 2016.
We will be watching this area of research very closely. Fingers crossed!