The PASADENA study announcement (part 2)

# # # # In April of this year it was announced that the closely watched Phase II PASADENA clinical trial had not to met its primary objective. This was a large clinical evaluation of an immunotherapy approach (called prasinezumab) for disease modification in Parkinson’s.  At the time of the announcement, it was indicated that the researchers who conducted the study had seen “signals of efficacy” in the data. This week the results of the study were presented at an international conference and it was reported that prasinezumab “significantly reduced decline in motor function by 35% (pooled dose levels) vs. placebo after one year of treatment“. In today’s post, we will discuss what the PASADENA study was, review the results that have been released, and discuss what might happen next. # # # #

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At 7am (just prior to the opening of the Swiss Stock Exchange) on Wednesday 22^nd April 2020, the pharmaceutical company Roche published its sales results for the 1^st Quarter. The financial report looked good, particularly considering the current COVID-19 economic climate, but there was one sentence on page 133 of the results (highlighted below) that grabbed a lot of attention:

From page 133. Source: Roche

For those of you (like myself) who struggle with fine print, the sentence reads:

“Study did not meet its primary objective, but showed signals of efficacy“

This was how the Parkinson’s community found out about the top line result of the closely followed Phase II PASADENA study evaluating the immunotherapy treatment prasinezumab in individuals recently diagnosed with Parkinson’s.

Many within the Parkinson’s community were basically:

Yet another negative clinical trial result.

But then, later that same day, the biotech firm Prothena – which developed prasinezumab and is partnered with Roche in the clinical testing – kindly provided a press release.

And in that document, the company repeated that prasinezumab “showed signals of efficacy” , but importantly: “These signals were observed on multiple prespecified secondary and exploratory clinical endpoints“.

And then the Parkinson’s community was like:

This week we found out more about those “signals of efficacy” and the results of the PASADENA study, and they look interesting.

What do the results show?

The PASADENA study is an ongoing Phase II clinical trial of the alpha synuclein-targeting immunotherapy treatment prasinezumab (the study is listed on the Clinicaltrials.gov as NCT03100149). For those readers unfamiliar with immunotherapy, prasinezumab and the PASADENA study – click here to read a previous SoPD post on this topic.

The study involves three parts (it used to be 2, but encouragingly it is now 3 parts):

Part 1 is a randomised, double-blind, placebo-controlled study involving approximately 300 people with Parkinson’s (all less than 2 years since diagnosis) to evaluate the efficacy and safety of prasinezumab/PRX002 in people with Parkinson’s over 52 weeks. Participants were randomly assigned to one of three groups (low dose/1500 mg or high dose/4500 mg of prasinezumab/PRX002, or placebo treatment). The treatments was administered (via intravenous infusion) once every 4 weeks.

Part 1 of the study is completed and the announcement made this week is associated with this part of the trial.

Part 2 of the PASADENA study is a 52-week blinded extension phase in which participants from the placebo group of the study will be re-randomly assigned into one of two doses of prasinezumab on a 1:1 basis. This means that all participants will be on active treatment (prasinezumab). Participants who were originally assigned to an active dose continue at that same dose level for the additional 52 weeks.

Part 2 of the study is still ongoing. The results that have been presented to date are from Part 1 of the study.

The recently added Part 3 of the study will be an extension of Part 2 for potentially up to 5 years (Click here to read more about the details of the study).

What do the Part 1 results suggest?

As the April release reported, the results of Part 1 of the PASADENA study found that 52 weeks of prasinezumab treatment in Parkinson’s did not meet the primary endpoint of the study.

What does primary endpoint mean?

The primary endpoint of a clinical study is a pre-determined measure of whether the agent has an effect in slowing Parkinson’s progression).

The primary end point for Part 1 of the PASADENA study was “a difference in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score (Parts I, II and III) between treatment and control groups”. Important to understand that the primary end point here was a combination of Parts I, II and III of the MDS-UPDRS.

And as you can see from the graph presented below, the blue line of the placebo group travels along basically the same trajectory as both of the treatment groups. The trajectory is an increasing change in MDS-UPDRS score (left hand axis) over time (line the bottom axis), suggesting progression of overall Parkinson’s features:

Source: Prothena

But (and it’s a big BUT), when the researchers broke the data down into individual components of the MDS-UPDRS and they looked at just Part III of the the MDS-UPDRS, they noticed both of the prasinezumab treated groups performed better that the placebo group.

Wait. What is part III of the MDS-UPDRS?

Part III is the clinician-based rating scores of the motor features of Parkinson’s.

It has 33 items (in effect there is only 18 items, but several address which side of the body, or which limb is affected) that a clinician will assess and score.

And when the researchers looked at just the Part III results, this is what they found:

Source: Prothena

If you look at the blue line in the graph above, you will see that it is on a steeper trajectory than the black lines of the prasinezumab treated groups. And it is well above the red line, which represents the pooled data of both prasinezumab treated groups.

There are two potentially interesting phases in this data: first, the initial separation of the lines (between baseline and week 24), and then the second phase between week 40 and 52 where the prasinezumab treated groups appear to plateau (highlighted by the green oval).

The first phase begs the question: did the treatment have an immediate effect (Possibly peripheral? Maybe a reduction in inflammation?), and then the second phase prompts the obvious question can this apparent plateauing be maintained over time?

It will be interesting to see what happens in Part 2 of the PASADENA study, where everyone will be on the prasinezumab treatment. Will the part 1 placebo participants display similar patterns of responses as they shift to the prasinezumab treatment? And will participants who were on prasinezumab treatment during Part 1 continue to plateau during Part 2?

Interesting. Is this all that was reported?

No. There are other pieces of encouraging data presented in the PASADENA Part 1 results.

For example, the researchers also looked at the time to worsening of motor function. That is to say, how long did it take each participant to reach +5 points extra on their MDS-UPDRS Part III score. And here they found that the placebo treated group reached this mark sooner (50% of them at ~160 days) than the prasinezumab treated groups (at ~220 days). See the blue line (placebo-treated group) in the graph below is lower than the combined prasinezumab treated groups (red line), indicating more rapid progression in terms of motor features in the placebo group (compared to the prasinezumab treated groups):

Source: Prothena

And there was another interesting difference in the data: The researchers used brain imaging to assess changes in cerebral blood flow in different brain regions in 69 participants (22 in the placebo group and 47 in the prasinezumab treated groups). They found that the prasinezumab treated groups exhibited a reduction in decline in cerebral blood flow in a region of the brain called the putamen, which is badly affected in Parkinson’s.

In the image below you have bird’s eye views of the brains of an individual treated with placebo treatment (left) and another treated with prasinezumab (right). The top row of images is from baseline measures (before treatment began), and the bottom row of images were taken after 52 weeks of treatment. Red indicates high levels of blood flow and the squared areas are where the putamen is in the brain – it lies on both sides of the brain). You will hopefully see that the difference between the top and bottom image is greater for the left hand side images (placebo) than the right hand side images (prasinezumab-treated), indicating a bigger reduction in cerebral blood flow to the putamen in the placebo group (compared to the prasinezumab treated groups):

Less red in the placebo group. Source: Prothena

This difference is another bit of data suggesting that the prasinezumab-treated group had a reduction in the progression of certain aspects of their Parkinson’s.

What do you mean “certain aspects of their Parkinson’s”?

Well, the researchers did say that prasinezumab did not show any effect on:

• DaT-SPECT brain imaging (a measure of dopamine activity in the putamen)
• MDS-UPDRS Part I (non-motor experiences of daily living)
• MDS-UPDRS Part II (motor experiences of daily living)
• SE-ADL (Schwab and England Activities of Daily Living) Scale

In addition, all of the participants in the PASADENA trial were recently diagnosed cases of Parkinson’s, and they were not on any PD medication (such as L-dopa) at the start of the trial. Being on PD medication was actually an exclusionary factor for being enrolled in the study. The investigators kept track of when all of the participants finally initiated PD medication and there was no difference between the prasinezumab treated groups and the placebo-treated group with regards to initiating PD medication.

So as with the 2017 exenatide results (Click here to read a previous SoPD post about this), there are hints of something interesting potentially happening here, but it requires further investigations.

And luckily, further investigations are currently ongoing. As we mentioned above, these results are only from Part I of the PASADENA study. Part II (where everyone participating in the study is put on prasinezumab and followed for another 52 weeks) is ongoing. We will hopefully learn more about those results next year.

What is going to happen next with prasinezumab?

Roche and Prothena have concluded that their “findings support the potential of prasinezumab to slow underlying disease pathophysiology and clinical decline in patients with PD. Further investigations are warranted” (Source).

So hopefully we will learn soon about plans for some kind of follow up (maybe Phase III) trial.

So what does it all mean?

There is a furious debate in academic circles at the moment regarding immunotherapy targeting alpha synuclein in Parkinson’s. It is partly based on a mass grave yard of Phase 2 & 3 clinical trials in Alzheimer’s research. Dozens of immunotherapy approaches targeting the Alzheimer’s-associated proteins beta amyloid and Tau have failed to make a dent in the progression of dementia (except of course for Biogen’s aducanumab – click here to read more about that saga).

It is also based on theories that accumulation of alpha synuclein is resulting in a loss of function toxicity (the protein is no longer doing everything it should be doing, resulting in stress on the cell) rather than a gain of function toxicity (too much protein causing trouble).

As a result, a huge amount of attention has been focused on the PASADENA study as it is the first immunotherapy clinical trial to announce results in Parkinson’s. Another alpha synuclein-based immunotherapy trial being closely watched is the Biogen SPARK study (Click here to read a previous SoPD post about that study) as it too is in Phase II.

Whether the waring factions of academia are right or wrong will ultimately be decided by what happens in the clinical studies that are currently ongoing.

My guess is that they are both right (and wrong).

The results presented by Roche and Prothena this week are encouraging and deserve further analysis and discussion. I’ll let you know when we hear anything new.

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ADDENDUM –20/10/2020: Today both Roche and Prothena announced that they will be advancing their alpha synuclein immunotherapy agent Prasinezumab into a Phase 2b study in individuals with early Parkinson’s, starting early 2021.

 

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The banner for today’s post was sourced from Roche