Hi all,There are seven drugs to my knowledge that are approved...

Hi all,

There are seven drugs to my knowledge that are approved by the FDA for various forms of ALS / MND. They are Toferson/ Relyurio/ Radicava/Rilutek ( riluzole variant) Tiglutik ( riluzole varian
t) Exservan ( riluzole variant ) and Neudaxta.

I have found data on Radicava that states there is an ongoing trial on NFL levels. Relyurio ( no internet data on NFL) Neudaxta ( no internet data on NFL ).Below is somae information on Riluzole v NFL and Toferson.

Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients

Florence Esselin et al. CNS Neurosci Ther. 2022 Oct.

Conclusions: In this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.

Radicava/edaravone findings in biomark e rs from ALS (REFINE ALS): Protocol and study design

September 2020

Neurology: Clinic

Objectives Identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in ALS. Real-world treatment outcomes will also be reported. Methods This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study ( Clinicaltrials.gov ; NCT04259255 ) with at least 200 ALS patients who will receive edaravone for 24 weeks (6 cycles; FDA-approved regimen). All participants must either be treatment-naive for edaravone or be more than 1 month without receiving any edaravone dose prior to screening. Biomarker quantification and other assessments will be performed at baseline (prior to cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch TM and SOMAscan®), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King’s clinical staging, ALS Assessment Questionnaire, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation.

So an ongoing trial.

Neurofilament light-chain response during therapy with antisense oligonucleotide Toferson in SOD1-related ALS: Treatment experience in clinical practice

Thomas Meyer et al. Muscle Nerve. 2023

Results: Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment.

So how did we go ?

Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS

Gavin McCluskey et al 2023

This study states " The mean NFL concentration was much higher in those with MND overall, at 314.0 pg/mL compared to 67.7 pg/mL for disease controls and 73.0 pg/mL for healthy controls (p < 0.001 for both)".

So compared to Toferson who reduced NFL concentration to a figure of approximately 66% where does MPL fit.

It's hard to do a specific % mathematical figure as to a reduction in NFL results. But to my calculations which may be approximate we are travelling at a 10% reduction. Further dosage
parameters may influence that .

Neurol., 23 February 2022
Sec. Neuromuscular Disorders and Peripheral Neuropathies.

This study showed that serum NfL levels correlated with the disease progression rate as assessed by the decline in the ALSFRS-R and KCSS stages. These results were consistent with those of previous studies showing that serum or CSF NfL levels correlated with the parameters of disease severity, such as the decline on the ALSFRS-R.

So have we stopped the axonal damage. Unsure, have we slowed the MND progression. Looks like yes.

Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics

Arvin Behzadi et al 2021

The average control figure of NFL serum for MND patients is upward to 300 pg/ml with healthy control being 40 to 73 pg/ml.

Lets look at Toferson costs $200 K per year. Owned by Biogen. Riluzole Generic ( no patent ) PBBS Australia $40 for 50 tablets approximately.

The absolute key to this is can Monepantel reduce TDP-43 , if it can I can nearly guarantee that this drug ( owned by whoever) will be used in the future.

What is TDP-43 in MND?

One of the key features in almost all cases of MND ( 97%) , including the most common genetic form related to changes to the C9orf72 gene, is the accumulation of a protein called TDP-43 in the nerve cells of the brain and the spinal cord.

Mandrioli in the 2018 study, Rapamycin treatment for Amyotrophic lateral sclerosis :
noted that rapamycin combined with riluzole, a glutamate blocker, can clear the cytoplasmic TDP-43 aggregates through induced autophagy.

One key to this pathway is MEK 5 , mTOR inhibitors reduce MEK5 expression which suppresses TDP-43 toxicity via the mTOR-independent activation of the autophagy-lysosome pathway. ( It's complex to explain and all I can say is that both drugs are synergising the excess protein removal).

The science stacks up , we may make a huge difference.

Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway

Farnaz Bahrami, 2014

States , "
On the other hand, accumulation of acidic vacuoles with distinct chromatin morphology and an increase in punctuate localization of green fluorescent protein-LC3B, and MPL-induced changes in the expression of SQSTM1/p62 were all indicative of MPL-induced autophagy.

So in relation to above, if SQSTM1/p62 ratio affects TDP-43 it creates a ratio imbalance on TDP-43 to create misfolded proteins. Thus reduces MND.

It's the best I can come up with why MPL is working it's magic on our MND sponsored patients.

Kpax