https://clinicaltrials.gov/study/NCT04297683
Last updated 27/06/24
Hi all,
The list above for the Healey platform. Let's have a peek.
Zilucopan. The first treatment arm for zilucoplan ended early after futility analyses showed it was unlikely to be beneficial.“While this was disappointing, it actually in a way met the goals of the trial, which is really to screen out drugs rapidly. So we were able to end this regimen early, saving months of operational activities,” Sabrina Paganoni, MD, PhD, trial’s co-lead investigator.
Data from the second arm showed Verdiperstat failed to significantly slow ALS progression and that arm has also been discontinued.Findings from the third and fourth trial arms have been more promising, however.
The fourth arm, pridopidine failed to show an effect on ALSFRS-R scores or survival outcomes in the overall group, but promising trends were seen for patients with early, rapidly progressing disease.
Pridopidine also significantly improved objective measures of speech function in a pre-specified analysis.So far, zilucoplan, verdiperstat, and SLS-005 have been discontinued due to lack of effectiveness.
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370%2823%2900213-4/fulltext
Preliminary results announced from the recently completed Phase 2 Healey ALS Platform trial 38 indicate that CNM-Au8 treatment did not slow ALSFRS-R change following 24 weeks of treatment.
Why my thoughts,
1. It is absorbed slowly via the first pass metabolism.
2. It requires prolonged dosing to reach therapeutic levels
3. Not metabolised by the liver, instead via regional tissue .
4. Bioavailability is 1 to 10% as compared to MPL 31%.
5. The levels not consistently quantifiable in human whole blood samples until 3–4 weeks of continuous daily oral dosing at 30 mg.10 Tissue levels do not reach equilibrium until >6 months of daily oral dosing .
6. First 12-weeks of active treatment represented a subtherapeutic period window whilst drug became therapeutic.
7. Therefore, orally delivered CNM-Au8 is blood brain barrier penetrant, albeit at low levels.
Ok lets have a quick look at the problems of nanocrystals crossing the blood brain barrier effectively.
This article helps.
https://www.unsw.edu.au/news/2024/05/bypassing-the-blood-brain-barrier
Now let's have a squiz at efficacy of CNM-AU8.
1. Primary and secondary endpoints of their first trial were not reached, it is important to cautiously interpret the exploratory endpoints and OLE outcomes suggesting potential benefit favouring CNM-Au8 treatment, and for the purposes of hypothesis-generation only.
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314176/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494002/
In summary it comes down to statistical significance in my book.Monepantel is the autophagic drug of choice. The main problem with MND ALS is the removal of protein aggregation. Regeneration of synapses is futuristic and can be of benefit some time in the future. The research goes on.
SLS-005 Trehalose :It does cross the blood brain barrier.Trehalose induces autophagy in the brain by activating TFEB (transcription factor EB), which leads to lysosomal enlargement and membrane permeabilization. This process involves the activation of the calcium-dependent phosphatase PPP3/calcineurin, resulting in TFEB dephosphorylation and nuclear translocation. Trehalose upregulates genes related to lysosomal function and autophagy, promoting the clearance of misfolded proteins. However, there is controversy over its role, as some studies suggest trehalose may block autophagic flux, affecting the progression from autophagosome to autolysosome. ( In laypersons terms. The progression from autophagosome to autolysosome refers to a critical step in the autophagy process, where autophagosomes, which are double-membraned vesicles that sequester cellular debris, mature by fusing with lysosomes to form autolysosomes. This fusion allows the contents of the autophagosome to be degraded by lysosomal enzymes. The process involves various molecular regulators, including SNARE proteins, tethering factors, and RAB GTPases, which coordinate membrane dynamics and fusion. Disruptions in this process can lead to diseases such as neurodegenerative disease and cancer)
SLS-005, which contains trehalose, is administered intravenously, allowing it to bypass the first-pass metabolism that typically occurs in the liver and intestines. This administration route ensures that trehalose can reach systemic circulation without being significantly metabolized, maintaining its efficacy in crossing the blood-brain barrier and exerting its therapeutic effects.
The trials involving SLS-005, a treatment for amyotrophic lateral sclerosis (ALS), the relationship with ALSFRS-R scores showed mixed results.
Overall, SLS-005 did not significantly slow ALS progression compared to placebo, as both groups experienced similar monthly declines in ALSFRS-R scores.
However, in a subgroup of patients not receiving AMX0035 (Relyvrio), SLS-005 showed a 22% improvement in the ALSFRS-R slope adjusted for mortality, indicating potential benefits in this specific group.
Monepantel according to Pharmaust announcement dated 26/08/24." Monepantel reduced the rate of ALS decline by 43.2% . Measures a decline of -0.25 to -0.45 points per month"
So what eventuated.
https://alsnewstoday.com/news/infusion-therapy-sls-005-fails-slow-als-progression-trial/
DNL-343 DNL-343 effectively crosses the blood-brain barrier and is extensively distributed to the central nervous system. This characteristic allows it to inhibit the integrated stress response pathway, which is implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
Generally, first-pass metabolism can reduce the concentration of a drug before it reaches systemic circulation, potentially affecting its efficacy. However, DNL-343 is described as a CNS-penetrant small molecule designed to inhibit the integrated stress response, suggesting that it effectively reaches its target in the brain.DNL343 is an investigational oral small molecule developed by Denali Therapeutics for the treatment of amyotrophic lateral sclerosis (ALS).
It targets eIF2B, a central regulator of the integrated stress response (ISR), which is overactive in ALS. DNL343 has shown promise in preclinical and early clinical trials by reducing cellular stress responses and dissolving harmful TDP-43 stress granules associated with ALS pathology. Interim data from a Phase 1b trial indicated that DNL343 is generally well-tolerated, and it is now part of the HEALEY ALS Platform Trial to further assess its efficacy.
My thoughts are inconclusive and debatable.They go along these lines till proven otherwise.
This is a new 2024 study which shows the effects of targeting eIF2B.
https://pubmed.ncbi.nlm.nih.gov/37823684/
Do no more harm !
So it has potential, but safety and long term issues need research.
Unsure how to rate this one yet as clinical data is limited in relation to ALSFRS scores and longevity in the disease process.
ABBV-CLS-7262 has been shown to enter the cerebrospinal fluid (CSF) at concentrations that can fully activate its target, eIF2B, suggesting it can cross the blood-brain barrier (BBB) to some extent. However, specific data on its penetration into brain tissue beyond the CSF is not detailed in the provided search results. The presence in CSF indicates some level of BBB crossing, but it does not confirm distribution into brain parenchyma.
It is similar to DNL-343.ABBV-CLS-7262 has been reported to have non-serious adverse effects, such as nausea, itchiness, constipation, dizziness, and headache, in clinical trials. These side effects were generally similar between those treated with ABBV-CLS-7262 and placebo, indicating no specific adverse effects directly related to its interaction with the blood-brain barrier.
Though I have searched results they do not provide specific information on the impact of ABBV-CLS-7262 on ALSFRS-R scores. The ALS Functional Rating Scale-Revised (ALSFRS-R) is a common measure used to assess disease progression in ALS clinical trials, but detailed outcomes related to ABBV-CLS-7262's effect on these scores are not mentioned in the available data.
The effectiveness of ABBV-CLS-7262 in slowing disease progression in ALS patients is currently being evaluated in clinical trials, including the HEALEY ALS Platform Trial.
This trial is assessing disease progression using the ALS Functional Rating Scale-Revised (ALSFRS-R) as a primary outcome. However, specific results regarding its effectiveness in altering ALSFRS-R scores or slowing disease progression have not yet been published, as the trial is ongoing and expected to complete in September 2024.
So another compound targeting eIF2B.As per the previous compound DNL-343 this study is pertinent unless further studies negate the findings.
https://pubmed.ncbi.nlm.nih.gov/37823684/
Is there any reason why we can't slot straight in to the Healey Platform?
Kpax
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