SPARK - BIIB054 (mostly for Gio)

[WinnieThePoo]

When Gio asked me to post something , I thought I had posted about this before, but reviewing my posts they are all short and flippant. I'll take this in small bites

I am one of 311 participants around the world in a quad blinded, multi-centre phase II trial known as SPARK, of a monoclonal alpha-synuclein antibody.

Alpha-synuclein (a-syn) has long been thought to be a possible cause, or part of the cause, for neuron damage in PD. Specifically it is the mis-folded forms of this protein which are thought to be the problem. The protein in its healthy form is a monomer, but in some people it aggregates into fibrils and eventually Lewy bodies

scienceofparkinsons.com/201... provides a good explanation about this.

A-syn is further associated with PD in that aggregated forms are found in higher levels in PWP. For example, one suggested early detection test was for A-syn in tears (in your eyes)

However, there has recently been some controversy about A-syn - it makes up much less of Lewy bodies than previously thought. Also, there has been a suggestion that its presence in PWP is the bodies healing reaction to the agent causing the neuron damage. The presence of aggregated A-syn is definitely associated with PD, but it might be like paramedics are usually found at the scene of road accidents. It doesn't mean they caused them.

For all that, there is a large body of thought that A-syn is the assassin, and not the paramedic. One idea is it can spread in a prion like way - contaminating adjacent molecules.

So the idea behind this trial is to try to remove bad A-syn, protect neurons, and slow or stop the progression of the disease. More to come...

[WinnieThePoo]

So "monoclonal a-syn antibody". This is basically an immunotherapy - but a passive one. Antibodies are produced by our bodies to latch onto and neutralise harmful substances. The most common immunotherapies I am aware of are active vaccines - usually a dead virus is injected which lets the body produce antibodies without being at risk from a live pathogen

BIIB054 is a passive immunisation. It takes existing antibodies and clones them and then those are administered via an intravenous drip for an hour every 4 weeks. These antibodies have been found to be VERY effective at binding to , and neutralising, the harmful aggregated forms of a-syn. However, in addition to the uncertainty about a-syn's role in PD, it is not known how well this monoclonal antibody crosses the blood brain barrier

The tests being carried out at the 4 weekly visits include lumbar punctures (for most, not me - I opted out) which show how well the drug is getting into the CSF - an indicator of penetration into the brain

The trials primary results are safety based - number of Adverse Events (AE), and Serious Adverse Events (SAE). My impression is that the trial is finding very few if any AE or SAE. As far as I am aware there are none in the 6 participants at Toulouse.

The trial is ongoing, but (COvid 19 disrupted) due to complete its first phase this month. For the first phase participants were randomly allocated to one of 4 streams

1)placebo

2)250mg

3)1250 mg

4)3500mg

At the end of year 1 (Feb 6th 2020 for me) the participants in stream 3&4 continue in the same stream. But the participants in stream 1&2 are allocated randomly to stream 3 or 4.

So in the 2nd year of the trial, every participant is on an active dose

For what little its worth, my guess is I was in stream 1 or 2 for the first year and in February changed to 3 or 4

[Gioc in reply to WinnieThePoo]

Thanks Richard, for responding so quickly to my request. We are certain that the villain is the alpha-synuclein in order not to widen the discussion too much and I want to put this discovery "to the hard test" and I quote you: "BIIBO54 is a passive immunization. It takes existing antibodies and clones them and then those are administered via an intravenous drip for an hour every 4 weeks. These antibodies have been found to be VERY effective at binding to and neutralizing, the harmful aggregated forms of a-syn. ".

But how did they find this antibody ?, did they create it from scratch? How do they know it is very effective against alfasyn.? Other questions will follow, I invite everyone to participate if it suits you. thanks Gio

[WinnieThePoo in reply to Gioc]

You're welcome Giovanni

How did they find it?

In 2010, Biogen licensed BIIB054 from Neurimmune (see company press release). The antibody was generated with reverse translational medicine technology from naturally occurring, presumably protective antibodies found in healthy aged donors, as were aducanumab and other antibodies in the Biogen-Neurimmune partnership

(This is a bit like the covid19 therapy being used in UK hospitals, taking antibodies from covid19 ITU survivors and giving them to new patients)

How do they know its very effective against a-syn?

As well as original lab tests, a phase 1 trial was carried out

clinicaltrials.gov/ct2/show...

In addition there has recently been a new study (with mice, but interesting), published in may 2019. This confirmed the effective selective binding to a-syn and showed BIIB054 treatment in mice reduces spread of pathology and improves motor function.

sciencedirect.com/science/a...

[Gioc in reply to WinnieThePoo]

Thank you Winnie, very interesting.

another question: We know a-syn has different forms, monomer, oligomer, fibrils. Which of these forms does BIIB054 affect and why should it be more effective than other similar antibodies being tested?

[WinnieThePoo in reply to Gioc]

Gio

Point 2 in the summary in the sciencedirect link - from the new mouse trial was

"BIIB054 shows ≥800-fold higher binding to aggregates than monomer."

It is impossible for me to say how effective it will be compared with other monoclonal antibodies being trialled . We await the results. It will be a great thing if just one of these new immunotherapies is effective

Compared with Prothena which Redhawk1 trialled it has a longer half-life and is more specialised to the aggregated forms of the protein.

I share redhawks view that he is not being invited to extend his trial participation to establish that an unmarketable product with no potential therapeutic benefit is really really safe. Why extend a trial if there are no benefits?

Similarly, we have been informed that we will be invited to continue using the drug at the end of the original trial period (much to the dismay of my nursing team, who every visit struggle to find a useable vein to administer the product)

[Gioc in reply to WinnieThePoo]

Thanks Winnie ,

Some studies suggest that the most harmful type of a-syn is in the form of an oligomer, but I could be wrong.

1. But let's move on to the difficult questions, it seems that BIIB054 has difficulty passing the Blood-Brain Barrier and that the dose should be higher, isn't it?

2. In a well presented study in the scientific media, carried out with considerable use of machinery (dat-scan and MRI), with infusions and monthly meetings with high level medical teams, aren't you afraid that the placebo effect is very high and that it obscures the results?

3. At very high doses could the safety of the drug be affected in the long term?

[WinnieThePoo in reply to Gioc]

Hi Gio

1). The proportion of the drug reaching the CSF is around 0.4%. That would mean about 14mg from the 3500mg dose. My guess is that 3500mg (for a 90kg adult) is going to be the effective dose if this drug turns out to be effective. That's why they're doing the trial

Note - the original protocol design was for cohort 1 (placebo) to switch to 2,3, or 4 in year 2, and for cohort 2 to remain on 250mg. They changed to the current version in May 2019 (my 4th infusion) following completion of the phase IIa part of the trial. My conclusion is 250mg clearly was doing nothing, so they wanted more safety data for the other 2 "effective" doses

So the trial doses are likely to be safe and well tolerated.

2) There is bound to be a massive placebo effect. There always is with Parkinsons research. And I have a personal team and get massive attention on an infusion day, and then follow up phone calls, a dedicated advice hotline...

But the duration of the trial is enough to eliminate the placebo effect if there are statistically significant results (active cohorts v placebo), and the trial is quad blinded and has 300+ participants at more than 10 sites.

My constipation relief in Yr2 could easily be a placebo effect (but as Royprop once said - I'll take a good placebo effect). Placebo effects can be very real physiologically. But it is VERY evident, and covid19 has given me the opportunity to experience it twice. Obviously no useful firm conclusions can be drawn from just my experience - but the final trial result from 300+ participants will look to distinguish placebo from active.

3)There appear to be no issues with safety at the trial doses - either AE's or SAE's. I get absolutely no side effects at all. In a very small sample in the initial phase 1 trial , there were no issues up to 90mg/kg (that would be 8000mg for me) but they had issues at 135mg/kg. My guess is 3500mg (45mg/kg) is adequate and safe

Allowing us to stay on the drug after the trial ends will allow them to get longer term safety information much earlier than if they had to wait for a new phase 3 trial to be designed, and recruited and implemented. It may even allow them, if the Datscan results are clearly statistically significant to move to a phase 3 trial in the field (ie to launch/licence after phase 2 under one of the expidited programs)

We should find out this time next year. Meantime, I'm happy to be back on it. Even if that is just placebo effect

[Gioc in reply to WinnieThePoo]

Hi Richard, thanks again,

as far as I know the placebo effect is much less pronounced on nomotor symptoms of PD, and it could be good news for you and everyone.

I have no more questions, thank you for the answers and for your great generosity for participating in this study.

Keep us updated, a greeting from Italy.

Gio

[redhawk1 in reply to WinnieThePoo]

Hi Winnie . . . I too have been closely following your progress in the Biogen Spark trial. Last September I completed my participation in the phase 2 Roche Prothena Pasadena clinical trial . . . the explanation of results of which were indeed nebulous.

As far as I know there have been no serious adverse events from receiving this medication.

As I recall, Winnie, after about 2 weeks of receiving the infusion my symptoms seemed to worsen. The half-life of this medication from what I have heard is 14 days or so.

Now, I have been asked if I want to continue the trial into a third year. Thus, Roche must be seeing some positive outcomes which would make them decide to continue this trial.

Have you seen a lessening of symptoms since restarting your infusions?

[WinnieThePoo in reply to redhawk1]

The main symptom which causes me to think my 2nd year cohort is different from the first is vanishing constipation.

My wife thinks I'm less grumpy, but that is outrageous nonsense, of course.

Equally, the primary idea was that it would stop or slow progression and so you wouldn't necessarily expect to notice immediate symptomatic relief. My disease progressed last year, which would be expected in cohort 1 or 2.

[jimcaster]

Thank you for the excellent explanation and for participating in the study. I don't want to dwell on the negative, but I am struck by your excellent analogy: "but it might be like paramedics are usually found at the scene of road accidents. It doesn't mean they caused them." I hope the widespread focus on alpha synuclein in Parkinson's disease isn't similar to the long term and hugely unsuccessful focus on beta amyloid in Alzheimer's disease. Fortunately, the SPARK trial should help shed light on that very concern.

Thanks again and good luck!

[kaypeeoh in reply to jimcaster]

I was diagnosed with MS based on an MRI. I was put on tysabri for well over a year. Tysabri is a monoclonal antibody. It's thought that abnormal white blood cells can cross the BBB and damage myelin. Tysabri binds to the abnormal cells preventing them from crossing the BBB. I quit the tysabri after follow-up MRIs showed no change in my brain, that is no increase in MS lesions. I remember the doctor saying, "We looked at your brain and found nothing."

[WinnieThePoo in reply to kaypeeoh]

In the case of PD finding no change is the golden egg. Without intervention PD is progressive. This trial is using 6 monthly datscans to evaluate

[WinnieThePoo in reply to jimcaster]

Yup. If it fails to provide a useful therapy it will add a lot of data to the a-syn debate. The pendulum seems to have swung back a little recently towards assassin

[JayPwP in reply to jimcaster]

Dale Bredesen says lewy bodies and protein misfolding is a consequence and not the cause.

youtu.be/Sq7uVZ_0D3U(Not working as expected?)

[WinnieThePoo in reply to JayPwP]

Caution about Dr Bredesen. This guy not only works with Perlmutter (drperlmutter.com/the-empowe... he uses the same "unsound" techniques in published papers

ucsf.edu/news/2020/05/41743...

[JayPwP in reply to WinnieThePoo]

👍

[WinnieThePoo in reply to jimcaster]

Like I said - the pendulum is swinging back a bit

ncbi.nlm.nih.gov/pmc/articl...

[bassofspades]

Hi Winnie!

I am currently being courted by a research company for a trial that sounds exactly like your spark trial. Funny because biogens website says that trial is now closed. Im thinking of participating although I would like to opt out of the spinal taps too, if possible. Waiting for them to call me so I can ask them a bunch of questions. Do you have any suggestions as to what I should ask about? I'm encouraged by your feedback above. Thanks my good friend !

Edit...the recruiter emailed me back. It's a Lundbeck drug.

Lu AF82422 (alpha-synuclein mAb

Synucleinopathies

Lu AF82422 is a monoclonal antibody targeting alpha-synuclein. Misfolding, aggregation and extracellular spreading of alpha-synuclein is believed to play a major role in disease pathology and progression in Parkinson’s disease and other neurodegenerative disorders

[WinnieThePoo in reply to bassofspades]

Another monoclonal a-syn antibody, so the same idea, different molecule , different trial. Is it the existing phase 1 or a new phase 2 trial you are being courted for?

Apart from reading thoroughly the trial agreement, and understanding properly what is required from you, I have no particular suggestions.

The main question would be eligibility. SPARK required trial participants not to be on any parkinsons medication prior to starting, and not to anticipate a need for medication for at least 12 months from day 0

Oh - and make sure you have veins that can be found!

[bassofspades in reply to WinnieThePoo]

Not sure what phase they're in . Waiting for them to call me back. Thanks my friend!