Celebration Thread! AMX0035 PDUFA Sep 29

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J11
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Celebration Thread! AMX0035 PDUFA Sep 29

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Potential AD treatments are popping up all over the place!
AMX0035 is one of them.

AMX0035 (sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine) by Amylyx is a treatment that is now before the FDA for approval. Originally the decision date was set for this month, though the FDA wants to think about it some more and has set the PDUFA date as September 29, 2022.

The ADCOMM vote was 4 votes in favor of approval 6 against. However, the clinical trial results are evolving and a phase 3 trial is now underway. By September definitive evidence might then be available and a possible approval.

What is of great interest to the AD community is that this product might then be available to them off-label. At the least there would be a self-supporting financing model to move it forward to help those with AD. An AD phase 2A trial (Pegasus) with the product was reported last year and features associated with AD (e.g. Beta-amyloid) appear to have been positively affected.

This is a fantastic development that I wanted to highlight with its own thread.
Last edited by J11 on Wed Jun 15, 2022 3:42 pm, edited 2 times in total.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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Hmm, they approved it?
Yeah!

Celebration Time!

Not really sure how this can count as a true J11 celebration thread!?
There are only 2 posts?
... and the second post (this one?) announces the approval?
Seems almost too easy!


On Monday June 13, 2022 Health Canada approved Albrioza (AMX0035 (sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine) )) for ALS! The reassigned FDA PDUFA date continues and is September 29, 2022

This is an Alzheimer adjacent approval; it could be helpful for those coping with amyloid dementia as there are shared pathways of pathology. A phase 2A clinical trial in AD was reported at CTAD 2021 (Pegasus) and it was generally favorable, as favorable as a phase 2A can be expected to be. Amylyx can now bank up and presumably invest in AD trials for the potential market of 55 million people with clinical Alzheimer's, while at the same time deepening the clinical knowledge base in ALS and possibly other neurodegenerative illnesses.

I had not expected that Canada would grant approval over America's veto. Perhaps this could be the go to strategy in the future when there is regulatory uncertainty-- this approval is unlike that of Aducanumab's as there is much less safety concern with Albrioza.

https://www.amylyx.ca/media/amylyx-phar ... ent-of-als
Last edited by J11 on Wed Jun 15, 2022 3:44 pm, edited 2 times in total.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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For reference below is the CTAD 2021 abstract for the phase 2A Pegasus Study of PB/TURSO in AD. Notice how biomarkers of AD pathology were positively affected by treatment.





A FIXED-DOSE COFORMULATION OF SODIUM PHENYLBUTYRATE AND TAURURSODIOL (PB/TURSO) FOR THE TREATMENT OF ALZHEIMER’S DISEASE: RESULTS FROM THE PHASE 2A PEGASUS STUDY.


Steven E. Arnold1, Suzanne Hendrix2, Jessie Nicodemus-Johnson2, Newman Knowlton2, Alison J. Mcmanus1, Monica Crane3, Sanjeev N. Vaishnavi4, Jeffrey M. Burns5, Zoe Arvanitakis6, Judith Neugroschl7, Victoria J. Williams8,
Rudolph E. Tanzi9, Patrick D. Yeramian10, Kent Leslie10

(1. Department Of Neurology, Massachusetts General Hospital, Boston, Ma - Boston (United States), 2. Pentara Corporation, Millcreek, Ut - Millcreek (United States), 3. Genesis Neuroscience Clinic, Knoxville, Tn - Knoxville (United States), 4. Department Of Neurology, Perelman School Of Medicine At The University Of Pennsylvania, Philadelphia, Pa - Philadelphia (United States), 5. University Of Kansas Alzheimer’s Disease Center, Kansas City, Ks - Kansas City (United States), 6. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Il - Chicago (United States), 7. Department Of Psychiatry, Icahn School Of Medicine At Mount Sinai, New York, Ny - New York (United States), 8. Department Of Medicine, University Of Wisconsin-Madison, School Of Medicine And Public Health, Madison, Wi - Madison (United States), 9. Sean M. Healey And Amg Center For Als & The Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Ma - Boston (United States), 10. Amylyx Pharmaceuticals, Inc., Cambridge, Ma - Cambridge (United States))


Background: An oral, fixed-dose coformulation of sodium phenylbutyrate (PB) and taurursodiol (TURSO) was designed to reduce neuronal death by simultaneously mitigating endoplasmic reticulum and mitochondrial dysfunction. Coformulated PB/TURSO was shown to significantly slow functional decline and prolong survival in a placebo-controlled trial in amyotrophic lateral sclerosis (CENTAUR). Preclinical evidence suggests potential activity of PB and TURSO individually in Alzheimer’s disease (AD). PB has been shown to reduce hippocampal neurodegeneration and amyloid plaque burden in murine AD models, with concordant improvements in spatial memory tasks. TURSO ameliorated amyloid deposition, reduced glial activation, and prevented cognitive decline in a double-transgenic murine model expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1 (APP/PS1). PEGASUS (NCT03533257) is the first clinical trial to evaluate PB/TURSO in AD. Objective: Assess the safety, tolerability, neurobiological activity, and preliminary clinical effects of PB/TURSO in a broad range of patients with dementia or mild cognitive impairment (MCI) due to AD over 24 weeks.


Methods: PEGASUS was an early phase 2, multicenter, randomized, double-blind, placebo-controlled trial enrolling adults aged 55–89 years with AD or MCI accompanied by biomarkers supporting AD pathology (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] AD biomarkers, fluorodeoxyglucose PET, or volumetric magnetic resonance imaging [vMRI]) and baseline Montreal Cognitive Assessment (MoCA) score ≥8. Participants were randomized to receive PB/TURSO or matching placebo for 24 weeks. Use of standard-of-care AD medications was permitted in participants on stable dosing regimens. MRI scans and lumbar punctures were performed on each participant at baseline and week 24. The primary objective was safety and tolerability of PB/TURSO compared with placebo. The primary efficacy outcome was a global test statistic for change from baseline to week 24 in 3 end points: Mild/Moderate Alzheimer’s Disease Composite Scale (MADCOMS), Functional Activities Questionnaire (FAQ), and hippocampal vMRI. Secondary efficacy outcomes included changes from baseline in clinical assessments, including MADCOMS, the 14-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog14), MoCA, the Dementia Severity Rating Scale (DSRS), FAQ, and the Neuropsychiatric Inventory Questionnaire, and in neuroimaging assessments, including regional brain volumes, white matter, and functional connectivity.

Biomarker outcomes included changes in core AD biomarkers (amyloid beta species [Aβ1-42 and Aβ1-40], total tau [t-tau], and phospho-tau 181 [p-tau]) in CSF, as well as other biomarkers of neuronal injury, oxidative damage, and inflammation. Mean changes from baseline to week 24 were compared between active and placebo arms for all efficacy outcomes and declared significant at the P<0.05 level. No hypothesis testing was performed for safety variables.

Results: A total of 95 participants were randomized (PB/TURSO, n=51; placebo, n=44). The average participant age was 70.7 years; approximately 80% of participants were receiving concomitant acetylcholinesterase inhibitors and 42%, concomitant memantine. Mean (SD) cognitive assessment scores indicated a significantly greater baseline level of cognitive impairment among those randomized to PB/TURSO versus placebo (ADAS-Cog14 total score, MOCA, and MADCOMS, all P<0.01). The PB/TURSO group had a numerically higher percentage of apolipoprotein E ε4 carriers compared with the placebo group (77.1% vs 61.4%, respectively; P=0.12). Baseline values for all other measures were similar between groups.


Treatment-emergent adverse events (TEAEs) were reported in 34 (67%) participants in the PB/TURSO group and 26 (59%) participants in the placebo group, with gastrointestinal events (primarily diarrhea) accounting for the greatest proportion of TEAEs in the PB/TURSO group (39% vs 14% in the placebo group). Ten of 51 (20%) participants in the PB/TURSO group and 2 of 44 (5%) participants in the placebo group discontinued study. No significant between-group differences were observed for the primary or secondary end points.

Changes in core AD biomarkers were found to be significant, with reductions in CSF t-tau (P=0.0005) and p-tau (P=0.0008) over the 24 weeks in the PB/TURSO versus placebo group and an increase in Aβ1-42/Aβ1-40 (P=0.017).

Conclusions: PB/TURSO was associated with a greater incidence of primarily gastrointestinal events compared with placebo, in line with previous clinical trial experience. While the study was not powered to test differences between groups in efficacy outcomes, no differences were found. There was suggestion of PB/TURSO activity on biomarkers of AD pathology (t-tau, p-tau, and Aβ1-42/Aβ1-40).


Analyses of additional CSF biomarkers and imaging sequences are planned to further understand the effects of PB/TURSO in patients with AD. Disclosures: Conflicts of interest will be listed in the presentation at CTAD.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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Two posts and the thread is finished?
We at least need a party announcement even if belated!

2022!

This is the golden era of Alzheimer clinical research!
Everything is happening right now!

We could have 3 (or more) positive readouts/approvals within months! (We have already had one; this one Albrioza. There is also LMTM; Lecanemab/Gantenerumab; possibly even some others.)

This is so large!

Normies have no idea about the Alzheimer Revolution that is underway. Prepare for the super-aging society.

https://www.timeanddate.com/countdown/p ... nt=cursive
Last edited by J11 on Fri Jun 17, 2022 6:05 pm, edited 2 times in total.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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J11 wrote: Wed Jun 15, 2022 10:04 am Hmm, they approved it?
Yeah!

Celebration Time!

Not really sure how this can count as a true J11 celebration thread!?
There are only 2 posts?
... and the second post (this one?) announces the approval?
Seems almost too easy!
Hi J11, with the tremendous effort you put into following all the treatment trials, you deserve a short and easy thread now and then! Thanks for keeping up with the research and posting your summaries and insights (and enthusiasm !) for the benefit of the whole community.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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Thank you flora. Stop.

Can't chat too long because they need me for the conga dance and I guess also another round of limbo. Stop.

Just too much to celebrate now. I have the countup party for Albrioza; also the countdown for the launch party for the LMTM results at AAIC; and also the countdown for the retirement party for the Lecanemab results after Clarity. Stop.

Can life just be too good? Stop.

Wish you were here.
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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J11 wrote: Fri Jun 17, 2022 5:49 pm Thank you flora. Stop.

Can't chat too long because they need me for the conga dance and I guess also another round of limbo. Stop.

Just too much to celebrate now. I have the countup party for Albrioza; also the countdown for the launch party for the LMTM results at AAIC; and also the countdown for the retirement party for the Lecanemab results after Clarity. Stop.

Can life just be too good? Stop.

Wish you were here.
Counting up, counting down

…..Limbo lower now!

Sorry to be missing out on the fun!
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Re: Celebration Thread! AMX0035 PDUFA Sep 29

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Update is that the FDA approved Amylyx's RELYVRIO. What I find of particular interest is the $157,000 per year price tag. What is the label is broadened to include AD? A phase 2 in AD has already been completed and it was encouraging. Amylyx could bank up and then advance its product into AD. One might expect that if it were approved in AD then the drug cost could be reduced a fair amount. Once AD biotech is fueled up with money, turbocharged progress becomes possible.

Yet, AD economics clearly could become worrisome very quickly. When you embrace the cocktail of medicine approach to treating illness, the actual final bill can become overwhelming. Consider that the all in price for combination AD therapy with "standard of care" might soon be astronomical. If one were load up the buggy with Lecanemab, and LMTM and Blarcamesine and Albrioza (AMX0035) ... {Hmm, wasn't Relyvrio called Albrioza?}. The full price for treatment of AD could be very large. At the same time on the horizon we also see the next generation of treatment that is more effective and cheaper. The big money aspect of biotech is a way of motivating the first movers to advance the science. Once they have been compensated, a more practical and economical standard of treatment emerges.
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