More effective access to the brain . . . probably what Biogen sees in partnering with Denali Therapeutics

[redhawk1]

Denali Therapeutics certainly seems to be in the “fast lane” in using their proprietary ETV technology to provide medications greater access to the brain. Biogen certainly seems to be betting that it will have a big impact! Positive news for PD medications getting to where they need to be!

apple.news/AOebcSEFtT8m_WQd...

[sharoncrayn]

DNL 151 is very narrow PD drug directed at PWPs with the LRRK2 mutation. They will ultimately go to a Phase 2 CT. Denali rejected moving forward with the sister drug DNL 201.

Old story. "Big impact"? perhaps.

Sharon

[Parkinsonjisung in reply to sharoncrayn]

sharoncrayn , i haven't looked into this, so maybe you can answer this faster. do you know what mechanism the drug is working on and what part having a LRRK2 mutation will play? Is the target specific to the mutation?

[sharoncrayn in reply to Parkinsonjisung]

151 and 201 were specific to this mutation. Denali isn't going to say specifically. Probably some form of inhibition o f LRRK2.

[redhawk1 in reply to sharoncrayn]

Hi Sharon . . . from my understanding the forthcoming Biogen/Denali trial featuring theDenali DNL 151 drug will also be open to sporadic PD cohorts as well as those with the LRRK mutation. I am currently one of those cohorts in the Roche/Prothena CT. So, when at my CT site to receive my every 28 day infusion I always ask those nurses/docs providing the CT services about other PD drugs they are trialing. Asking 3 different trialgivers all have said the response that all 5 cohorts to the Denali drug was “positive” to “very positive” . . . such words are not heard very often in this PD trial world. Biogen has been “around the block” a few times with such drugs so my guess (only a guess) is that they are seeing something very intriguing and maybe effective in either the DNL151 drug itself or the way it is being delivered to the brain.

[gwendolinej in reply to redhawk1]

Please keep us informed on how it’s going and your impressions and any improvements. Fingers crossed 🤞

[redhawk1 in reply to gwendolinej]

Speaking from my experience in the Pasadena CT it is very difficult, indeed, to discern how efficacious the Prothena drug has been as my PD symptoms have progressed, all be it slowly. Tough to compare and make that judgement when you have nothing with which to compare. Roche is continuing into another phase (2b) consisting of 575 cohorts so they must be seeing something positive in the reseults of phases 1 and 2.

[sharoncrayn in reply to redhawk1]

red,

results of Denali Phase 1 and 1b (and their expansions) were basically "safety" and tolerability trials. I might be wrong, but I doubt it. So, any efficacy conclusions are too early.

Open to other cohorts (sporadic) besides LRRK2 (not LRRK) is just common sense.

Roche's ongoing phase 2 evaluating prasinezumab (a-syn drug) is strictly an EARLY PD drug trial. Very good design with DaT-SPECT requirement. Parts 1 and 2 out to 104 weeks.

participants have UPDRS scores = early progression (20.5 average)

NO real conclusions of significance. "The PASADENA population can be considered representative of a wider PD population and therefore suitable for testing the potential beneficial effect of drugs acting on disease progression, such as prasinezumab" I would say "early",not wider.

"they are seeing something very intriguing " What? they don't say.

Sharon

[redhawk1 in reply to sharoncrayn]

Thanks for your response, Sharon! Always appreciate your thoughtful commentary!

[sharoncrayn in reply to redhawk1]

you are welcome

[Hidden in reply to sharoncrayn]

What is the best source for learning what the current trials are? And do you know how to determine what the funding needs are?

[sharoncrayn in reply to redhawk1]

if you are using their mobile monitor V2, you can/shouldrecord your daily (every 2nd day) results. it should tell you if the intervention is working or not. let us know what you find.

At week 24 and 52 they should let you know all your results, both + and - .

Sharon

[redhawk1 in reply to sharoncrayn]

The completed two-year phase 2 required the wearing of the mobile phone and frequent self testing. Now in phase 2b only required every 3 months at CT site visits.

[sharoncrayn in reply to redhawk1]

what are your results?

[redhawk1 in reply to sharoncrayn]

Hi Sharon . . .

[redhawk1 in reply to sharoncrayn]

Hi Sharon . . . started Pasadena trial September 2017. Not sure if I was on placebo or the drug for that first year. All were on medication second year. One year hiatus from trial . . . then after Roche examined results I was invited to continue trial in September 2020 and today just completed my seventh infusion in year three.

Symptoms have progressed, but “slowly” as I have nothing with which to compare of course. Currently not on any PD medication but that may come soon if symptoms worsen.

Apparently those in the Pasadena portion of the trial could continue for up to 5 years.

Aside from the trial I am in, Roche is beginning another trial using same med . . . and this time one may be on PD meds as well. Up to 575 in this trial.

So, here again, Roche must be seeing something efficacious as well. I just wish such positive effects were more pronounced. So . . . will continue “taking one for the team” . . .

[jimcaster in reply to redhawk1]

Thank you for participating in the trial and for sharing your experience, redhawk1. No matter what the ultimate outcome is, you are doing your part to increase the world's collective knowledge about PD.

[sharoncrayn in reply to redhawk1]

baseline UPDRS? vs UPDRS at 52 AND 104 WEEKS, etc.? I guess they aren't following their protocol.

[redhawk1 in reply to sharoncrayn]

Roche trial protocol required self testing with mobile phone each day (or as often as possible) and completion of the necessary PD tests when at site. DatScans and MRI at beginning and conclusion of trial. In addition blood draws and testing at every infusion. Skin tests twice! ouch! So, evaluation of cohorts was as thorough and well done as could be. I have looked for published results of the Pasadena trial but haven’t found much. I suppose Roche is reluctant to release such results for competitive reasons or not wanting to conclude any kind of success until verified by another larger trial . . . which is about to happen. That being said I would think Roche and Prothena have had to acquire much new knowledge from all the time and money spent! At least I would hope so!

[sharoncrayn in reply to redhawk1]

for individual participants, some CTs are very transparent; others are not. You are not in a transparent CT apparently. too bad.

you have been very generous of your praise for Roche. were you paid?

[redhawk1 in reply to sharoncrayn]

Hi again SC . . . just visited Prothena website news release area and found some late info just released. If you can find a moment in your busy work day your interpretation of results show cased would be welcomed!! Above my pay grade! lol. Thank you, Sharon

ir.prothena.com/news-releas...

[sharoncrayn in reply to redhawk1]

from Pagano's, (Roche employee), presentation of 18 Feb, 2021 re: Part 1

#1"Primary endpoint not met " (major negative, change from baseline of total UPDRS,1,2,3)

#2 AEs increased with esculation of dose (91% of cohort at 4500 high dose, 93% at 1500)...seen by Roche as "favorable".

#3 change in UPDRS 3 accounted for most of disease progression

#4 change in UPDRS 1 and 2 = none or minimal (confounding results by dose)

#5 MAO-B inhibitors-treated and diffuse malignant sub-phenotype( Much more than MAO-B) showed faster disease progression on MDS-UPDRS Part III, which is a negative.

#6 Slowing of clinical decline with prasinezumab was more evident in individuals with faster disease progression (diffuse malignant), which is a positive. Somewhat confusing given #5.

#7 NO scan results! why not?

Sharon

[redhawk1 in reply to sharoncrayn]

Thank you, Sharon, for helping to highlight some of the important trial results thus far. I thought I saw some mention regarding scan results previously but can’t find it. Yes. Information from trial has been nebulous at best,

[MarionP in reply to redhawk1]

What is the route? Maybe next time you see them you could ask them to define "cohort" and "positive" in objective terms? They already know from tags or markers that the molecules are delivered, absorbed, into the proper site? Or that it is "doing" "something"? (what)

parkinsonsnewstoday.com/202...